SEDATIVES

Sedative [anxiolytic] -Reduces anxiety -Little or no effect on motor or mental functions -Suppression of responsiveness to a constant level of stimulation -Decreased spontaneous activity and ideation

Hypnotic -Produces drowsiness -Encourage onset and maintenance of sleep

SEDATIVE HYPNOTIC DRUGS

1. Zolpidem
Indication & Dosage Oral Short-term management of insomnia Adult: As conventional release tab: 10 mg immediately before bedtime; max: 10 mg/day. As controlled release tab: 12.5 mg immediately before bedtime. Elderly: As conventional tab: Initiate with a 5-mg dose before bedtime. As controlled release tab: 6.25 mg immediately before bedtime. Hepatic impairment: As conventional tab: Initiate with 5 mg before bedtime. Severe: contra-indicated. Administration Should be taken on an empty stomach. (Do not take w/ or immediately after a meal.) Overdosage Symptoms: impairment of consciousness from somnolence to coma, compromised CV and respiratory function. Management: Treatment is largely symptomatic and supportive. Activated charcoal may be given if presented within one hour of ingestion of >100 mg zolpidem in adults and >5 mg in children. Gastric lavage may be considered if presented within 1 hr of ingestion of >100 mg zolpidem. Flumazenil may be used if there is severe CNS depression, but generally not needed. Haemodialysis unlikely to be useful.

1. Zolpidem
Contraindications Special Precautions

Severe hepatic insufficiency.

Obstructive sleep apnoea, myasthenia gravis, compromised respiratory function, hepatic impairment. Caution in patients exhibiting symptoms of depression. Patients should be warned from doing any work involving mental alertness or motor coordination after ingestion of the drug. Pregnancy and lactation. Re-evaulate if insomnia fail to remit after 7-10 days. Max duration of treatment: 4 wk including tapering. Amnesia, drowsiness, dizziness, diarrhoea, nausea, vomiting, abnormal thinking and behaviour, drugged feelings, back pain, ataxia, hiccups, confusion, euphoria, insomnia, vertigo, diplopia, abnormal vision. Potentially Fatal: Hepatitis, anaphylactic reactions, sleep-driving (driving while not fully awake after drug ingestion, with no recollection of the event).

Adverse Drug Reactions

Storage

Oral: Store at 20-25C (68-77F).

1. Zolpidem
Mechanism of Action Zolpidem acts by binding to the benzodiazepine (BZD) receptors of the GABA receptor complex. It has a selective affinity to BZD receptors prevalent in the cerebellum (omega-1 receptors). It has strong sedative actions but only minor anxiolytic properties. It has also less effects on skeletal muscle and seizure threshold. Zolpidem has a rapid onset but short duration of hypnotic action. Absorption: Rapidly absorbed from GI tract. Peak plasma concentration: 3 hr. Absolute bioavailability: 70%. Food reduce both the rate and extent of GI absorption. Distribution: Protein binding: 92%. Distributed into breast milk. Metabolism: Undergoes first pass metabolism, metabolised primarily by the cytochrome P450 isoenzyme CYP3A4. Elimination half life: 2.5 hr. Excretion: Excreted in urine and faeces as inactive metabolites.

MIMS Class ATC Classification

Hypnotics & Sedatives N05CF02 - zolpidem ; Belongs to the class of benzodiazepine related agents. Used as hypnotics and sedatives.

2. Bromisoval
Indication & Dosage Oral Sedation Adult: 0.2-1 g at night. Contraindications Elderly and debilitated patients; young adults, child; depression; pulmonary insufficiency; sleep apnoea; preexisting CNS depression or coma; severe hepatic impairment. Porphyria. Pregnancy and lactation. Elderly and debilitated patients; young adults and childn. Special Precautions Renal insufficiency; may cause paradoxical excitatory reaction when given to patients in pain unless an analgesic is given concomitantly; may impair ability to drive or operate machinery. Adverse Drug Dependence; drowsiness, sedation, ataxia; resp depression; Reactions headache; GI disturbances; skin reactions; confusion and memory defects; paradoxical excitement, irritability; hypersensitivity reactions; haematologic disorders. Nystagmus, miosis, slurred speech and ataxia in excessive doses. Potentially Fatal: Bromide accumulation and symptoms resembling bromism. Produces neonatal intoxication, vit K deficiency symptoms, congenital malformations when taken during pregnancy.

2. Bromisoval
Drug Interactions Sedation or resp depression may be enhanced by drugs with CNS depressants; MAOIs may prolong the CNS depressant effects and also reduce the convulsive threshold, thereby antagonise the anticonvulsant action of barbiturates. Others: Fenoprofen, methadone, pethidine and opioid analgesics; disopyramide, lidocaine and quinidine; chloramphenicol, doxycycline; warfarin and coumarin; antidepressants eg, bupropion, fluoxetine, lithium and mianserin; valproate and progabide; vigabatrin, oxcarbazepine, carbamazepine, clonazepam, ethosuximide, lamotrigine, tiagabine and zonisamide, griseofulvin; teniposide; metronidazole; chlorpromazine; HIV-protease inhibitors; blockers; calcium-channel blockers eg, nifedipine and verapamil; digitoxin; ciclosporin; corticosteroids; furosemide; montelukast; oral contraceptives; theophylline; levothyroxine; influenza vaccination and vitamins. Alcohol. St. John's wort. Bromisoval has actions and uses similar to carbromal, a bromureide which in turn have general properties similar to barbiturates. It was formerly used for its sedative and hypnotic properties. Hypnotics & Sedatives N05CM03 - bromisoval ; Belongs to the class of other hypnotics and sedatives.

Mechanism of Action MIMS Class ATC Classification

3. Chloral hydrate
Indication & Dosage Oral Insomnia Adult: 0.5-2 g as a single dose at night. Child: Neonate: 30-50 mg/kg; 1 mth-12 yr: 30-50 mg/kg (max: 1 g); 1218 yr: 0.5-1 g (max: 2 g). Dose to be taken at night. May be given rectally if oral route is not available. Elderly: Dose reduction may be required. Oral Sedation Adult: 250 mg tid. Max: 2 g daily Child: Neonate: 30-50 mg/kg; up to 100 mg/kg may be used with respiratory monitoring. 1 mth-12 yr: 30-50 mg/kg (max: 1 g); up to 100 mg/kg (max: 2 g) may be used; 12-18 yr: 1-2 g. Doses to be taken 45-60 minutes before procedure. May be given rectally if oral route is not available. Elderly: Dose reduction may be required. Contraindications Hepatic or renal impairment, cardiac disease, hypersensitivity, porphyria, oesophagitis, gastritis. Pregnancy and lactation. Special Precautions May impair ability to drive and operate machinery. Patients with mental depression, suicide tendencies, or a history of alcohol and drug abuse, or whose history indicates they may increase dosage on their own

3. Chloral hydrate
Adverse Drug Reactions Gastric irritation, abdominal distention and flatulence, vertigo, ataxia, staggering gait, rashes, malaise, lightheadedness, headache, ketonuria, excitement, nightmares, delirium (especially in elderly), eosinophilia, reduction in white blood cell count; dependence on prolonged use. Additive CNS depression with other CNS depressants such as paraldehyde, barbiturates. Furosemide or oral anticoagulants may increase the risk of side effects. Alcohol. Chloral hydrate may produce false-positive results for urine-glucose determination utilizing cupric sulfate e.g. Benedict's solution and possibly with cupric sulfate tablets, except urine glucose tests utilising glucose oxidase. It may interfere with fluorometric tests for urine catecholamines; Reddy, Jenkins, and Thron procedure for determining urinary 17-hydroxycorticosteroids.

Drug Interactions

Lab Interference

3. Chloral hydrate
Pregnancy Category Category C: Either studies in animals have revealed adverse effects on (US FDA) the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus. Mechanism of Chloral hydrate is used principally as a hypnotic in the treatment of Action insomnia; effective only for short-term use. Its CNS depressant effect, similar to those of paraldehyde and barbiturates, may be attributed to its metabolite, trichloroethanol. Onset: 30-60 min. Duration: 4-8 hr. Absorption: Rapidly absorbed from the GI tract after oral admin. Distribution: Passes into the CSF, breast milk and across the placenta. Metabolism: Rapidly metabolised to trichloroethanol and trichloroacetic acid in the erythrocytes, liver and other tissues. Excretion: Partly excreted in the urine as trichloroethanol and its glucuronide (urochloralic acid) and as trichloroacetic acid. Some is also excreted via the bile. MIMS Class Hypnotics & Sedatives ATC Classification N05CC01 - chloral hydrate ; Belongs to the class of aldehydes and derivatives. Used as hypnotics and sedatives.

4. clorazepate

Available Brand: Tranxene

Indication & Dosage Oral Anxiety Adult: 7.5 mg tid. Elderly: and debilitated patients: Initiate at lower dose and adjust slowly. Hepatic impairment: Initiate at lower dose and adjust slowly. Oral Alcohol withdrawal syndrome Adult: 90 mg daily in divided doses. Child: 9-12 yr old: 60 mg in divided doses. Elderly: and debilitated patients: Initiate at lower dose and adjust slowly. Hepatic impairment: Initiate at lower dose and adjust slowly. Oral Epilepsy Adult: 90 mg daily in divided doses. Child: 9-12 yr old: 60 mg in divided doses. Elderly: and debilitated patients: Initiate at lower dose and adjust slowly. Hepatic impairment: Initiate at lower dose and adjust slowly.

4. clorazepate
Overdosage Somnolence, impaired coordination, slurred speech, confusion, coma, and diminished reflexes, hypotension, seizures, respiratory depression and apnea also may occur. Treatment is symptomatic and supportive. Flumazenil, a benzodiazepine antagonist, may be used after evaluating the benefits and risks. If recent ingestion, emesis or gastric lavage followed by activated charcoal and a saline cathartic to remove any remaining drug. Monitor pulse, respiration and blood pressure. Admin IV fluids and maintain an adequate airway. IV norepinephrine or metaraminol may be used for hypotension. Haemodialysis is not likely to be useful.

Contraindications

Hypersensitivity (cross-sensitivity with other benzodiazepines may occur); narrow-angle glaucoma. Patients with depressive or psychotic disorders. child <9 yr. Pregnancy; lactation. Special Precautions Elderly, debilitated patients; hepatic disease, alcoholics; renal impairment; resp disease; impaired gag reflex; patients experiencing apnoea during sleep; operating machines or driving; patients on CNS depressant or psychoactive drug therapy; depression, esp those with suicidal tendencies; history of drugdependence.

4. clorazepate
Adverse Drug Reactions Jaundice, hepatic necrosis; extrapyramidal disorders; acute attacks of porphyria in porphyric patients, hypotension; drowsiness, fatigue, ataxia, lightheadedness, memory impairment, insomnia, anxiety, headache, depression, slurred speech, confusion, nervousness, dizziness, irritability; rash; decreased libido; xerostomia, constipation, diarrhoea, decreased salivation, nausea, vomiting, increased or decreased appetite; dysarthria, tremor; blurred vision, diplopia. Potentiates CNS effects of narcotic analgesics, barbiturates, phenothiazines, ethanol, antihistamines, MAO Inhibitors, sedativehypnotics, cyclic antidepressants. CYP3A4 inhibitors eg, amprenavir, cimetidine, ciprofloxacin, clarithromycin may increase serum conc and toxicity of clorazepate. Carbamazepine, rifampin and rifabutin may decrease clorazepate therapeutic effects by enhancement of clorazepate metabolism. Grapefruit juice increases serum conc or toxicity risk of clorazepate. Herbs or nutraceuticals eg, valerian, St. John's wort, kava kava and gotu kola may increase CNS depression upon concomitant admin with clorazepate.

Drug Interactions

Food Interaction

4. clorazepate
Pregnancy Category (US FDA) Storage Mechanism of Action Category D: There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Oral: Store at 15-30C. Clorazepate binds to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron within the central nervous system, limbic system, reticular formation resulting to an increase in chloride ion permeability which further leads to hyperpolarisation and stabilisation. Onset: 1-2 hrs. Duration: 8-24 hrs. Absorption: Following oral administration, complete absorption of the dose from the small intestine. Distribution: Crosses the placenta and small amounts appear in the urine. Metabolism: Rapidly activated to desmethyldiazepam via decarboxylation prior to absorption at low stomach pH; hepatic (as active oxazepam). Excretion: Via urine.
Hypnotics & Sedatives / Anticonvulsants

MIMS Class

5. midazolam
Indication & Dosage Oral Short-term management of insomnia Adult: 7.5-15 mg given at night. Oral Sedation for dental and minor surgical procedures Child: 6 mth: Single dose of 250-500 mcg/kg, up to a max of 20 mg. Younger patients (6 mth-<6 yr) may require up to 1 mg/kg. Oral Premedication in surgery Child: 6 mth: Single dose of 250-500 mcg/kg, up to a max of 20 mg. Younger patients (6 mth-<6 yr) may require up to 1 mg/kg. Intramuscular Premedication in surgery Adult: 70-100 mcg/kg (usual dose: 5 mg) given 20-60 minutes before surgery by deep IM inj. Child: 1 yr: 80-200 mcg/kg given 20-60 minutes before surgery by deep IM inj. Elderly: 20-50 mcg/kg given 20-60 minutes before surgery by deep IM inj. Parenteral Sedation for dental and minor surgical procedures Adult: IV admin: Initially, up to 2.5 mg given over at least 2-5 minutes, 5-10 minutes before procedure. Repeat after at least 2 minutes if necessary. Usual total: 3.5-5 mg. Max total: 7.5 mg.

5. midazolam
Indication & Dosage Child: IV admin: 6 mth-5 yr: Initial: 50-100 mcg/kg given over 2 minutes, increase slowly at 2-minute intervals up to a total of 600 mcg/kg, max total dose: 6 mg. 6-12 yr: 25-50 mcg/kg given over 2 minutes and increase slowly at 2-minute intervals up to a total of 400 mcg/kg; max total dose: 10 mg. IM admin (used only in exceptional cases): 1-15 yr: 50-150 mcg/kg; max: 10 mg. Elderly: Initially 1-1.5 mg given over 2 min, increased by increments of 0.5-1 mg at 2 min intervals as needed. Intravenous Induction of anaesthesia Adult: 150-200 mcg/kg by slow inj in premedicated patients and at least 300 mcg/kg for those who have not received a premedicant. Additional doses may be required to complete induction, up to 600 mcg/kg in resistant cases. Child: >7 yr: 150 mcg/kg. Max total: 500 mcg/kg (not >25 mg). Elderly: 100-200 mcg/kg in divided doses at 2-minute intervals. Intravenous Sedation in critical care Adult: Loading dose: 30-300 mcg/kg given as infusion over 5 minutes to induce sedation. Maintenance dose: 20-200 mcg/kg/hr. For patients with hypothermia, hypovolaemia or vasoconstriction: Reduce or omit loading dose, and reduce maintenance dose.

5. midazolam
Indication & Dosage Child: Neonates with gestational age <32 wk: 30 mcg/kg/hr by continuous IV infusion. Neonates with gestational age >32 wk and who are <6 mth: 60 mcg/kg/hr. 6 mth: Initial loading dose of 50-200 mcg/kg given by slow IV inj; maintenance dose of 60-120 mcg/kg/hr given as IV infusion. In obese paediatric patients, calculate dose based on ideal wt. Elderly: Dosage may need to be reduced. Rectal Sedation for dental and minor surgical procedures Child: >6 mth: 300-500 mcg/kg as a single dose. May dilute with water for inj up to a total volume of 10 mL if the volume is too small. Rectal Premedication in surgery Child: >6 mth: 300-500 mcg/kg as a single dose. May dilute with water for inj up to a total volume of 10 mL if the volume is too small. Special Populations: Dosage in intensive care may need to be reduced in patients with hypovolaemia, vasoconstriction or hypothermia. Reconstitution: Midazolam solution for injection may be administered rectally. The inj solution may be diluted with Water for Injections up to a total volume of 10 ml if the volume is too small.

5. midazolam
Administration Overdosage May be taken with or without food. Symptoms of overdose include sedation, confusion, impaired coordination, muscle relaxation or paradoxical excitation. More serious symptoms would be areflexia, hypotension, cardiorespiratory depression, apnoea and coma. Treatment is generally supportive and symptomatic. The benzodiazepine antagonist flumazenil is indicated in cases of severe intoxication accompanied with coma or respiratory depression. Caution should be observed in the use of flumazenil in case of mixed drug overdosage and in patients with epilepsy already treated with benzodiazepines. Acute narrow-angle glaucoma; coma or patients in shock; acute alcohol intoxication; intrathecal and epidural admin. Acute pulmonary insufficiency or marked neuromuscular respiratory weakness including unstable myasthenia gravis; severe respiratory depression.

Contraindications

5. midazolam
Special Precautions Paediatric patients with cardiovascular instability; chronic renal failure; open-angle glaucoma; cardiac disease; respiratory disease; myasthenia gravis; neonates; history of drug or alcohol abuse; elderly and debilitated (reduce dose); avoid prolonged use or abrupt withdrawal; hepatic impairment; severe fluid or electrolyte disturbances. May impair ability to drive or operate machinery; titrate dose carefully; monitor for early signs of hypoventilation, airway obstruction, or apnea. Pregnancy, lactation Physical and psychological dependence with withdrawal symptoms; decreased tidal volume and respiration rate; apnoea; headache; hiccup; nausea, increased appetite, vomiting; cough; oversedation; seizure-like activity (paediatrics); paradoxical reactions; kernicterus; nystagmus; skin rash, pruritus; reduced alertness, confusion, euphoria, hallucinations, fatigue, dizziness, ataxia, post-operative sedation, anterograde amnesia; jaundice; cardiac arrest, heart rate changes, thrombosis; anaphylaxis; laryngospasm, bronchospasm. Potentially Fatal: Respiratory depression, respiratory arrest; hypotension.

Adverse Drug Reactions

5. midazolam
Drug Interactions Increased CNS depression with alcohol, opioids, barbiturates, other sedatives and anaesthetics. Increased respiratory depression with opiates, phenobarbital, other benzodiazepines. Plasma concentrations increased by CYP3A4 inhibitors such as cimetidine, erythromycin, clarithromycin, diltiazem, verapamil, ketoconaz ole and itraconazole, antiretroviral agents, quinupristin with dalfopristin. Midazolam concentration decreased by phenytoin, carbamazepine, phenobarbital, rifampicin. Halothane, thiopental requirements may be reduced during concurrent use. Bioavailability of oral midazolam increased by grapefuit juice. Avoid concomittant use. Category D: There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective). Intramuscular: Store at 20-25C. At a final concentration of 0.5 mg/ml, midazolam is stable for up to 24 hr when diluted with 0.9% sodium chloride or 5% dextrose in water. Intravenous: Store at 20-25C. At a final concentration of 0.5 mg/ml, midazolam is stable for up to 24 hr when diluted with 0.9% sodium chloride or 5% dextrose in water. Parenteral: Store at 20-25C. At a final concentration of 0.5 mg/ml, midazolam is stable for up to 24 hr when diluted with 0.9% sodium chloride or 5% dextrose in water. Rectal: Store at 20-25C.

Food Interaction

Pregnancy Category (US FDA)

Storage

5. midazolam
Mechanism of Action Midazolam is a short-acting benzodiazepine. It exerts sedative and hypnotic, muscle relaxant, anxiolytic and anticonvulsant actions. While the probable anxiolytic action might be as a result of the drug's ability to increase glycine inhibitory neurotransmitter level, the hypnotic/anaesthetic action may be due to the occupation of the benzodiazepine and GABA receptors leading to membrane hyperpolarisation and neuronal inhibition, and further interfering with the re-uptake of GABA at the synapses. Absorption: Rapidly absorbed (any route); peak plasma concentrations after 20-60 min (depending on route). Distribution: Crosses the placenta; enters breast milk. Protein-binding: 96% Metabolism: Extensively hepatic via CYP3A4 isoenzyme; converted to hydroxymethylmidazolam. Excretion: Urine (as glucuronide conjugates); 2 hr (elimination half-life), prolonged in neonates, elderly and hepatic impairment. Anxiolytics / Hypnotics & Sedatives / Anticonvulsants N05CD08 - midazolam ; Belongs to the class of benzodiazepine derivatives. Used as hypnotics and sedatives.

MIMS Class
ATC Classification