Diazepam

Diazepam (中文: 地西泮) is a long-acting benzodiazepine with anticonvulsant, anxiolytic, sedative, muscle relaxant properties. It is used:

• In the short-term treatment of severe anxiety disorders;
• As a hypnotic in the short-term treatment of insomnia;
• As a sedative
• As an anticonvulsant (particularly in the management of status epilepticus and febrile convulsions)
• In the control of muscle spasms
• In the management of alcohol, or benzodiazepine withdrawal syndrome.

Pronunciation

Diazepam 2mg

Diazepam 5mg

Drug Names

Generic Name 藥名	HA Code 藥物代碼	Classification藥物分類
Diazepam Tablet 2 mg	DIAZ01	P1S1S3 & Part 1 Dangerous Drug
Diazepam Tablet 5 mg	DIAZ02	P1S1S3 & Part 1 Dangerous Drug
Diazepam Rectal Solution 2mg/ml (2.5ml/tube)	DIAZ10	P1S1S3 & Part 1 Dangerous Drug
Diazepam Rectal Solution 4mg/ml (2.5ml/tube)	DIAZ11	P1S1S3 & Part 1 Dangerous Drug

Mechanism of Action

• Diazepam is a benzodiazepine.
• Gama-Aminobutyric acid (GABA) is an inhibitory neurotransmitter, acting on the GABA receptors in the central nervous system (CNS), thus inhibiting the nerve impulses.
• It acts on the benzodiazepine receptors in the brain and the spinal cord. Benzodiazepine receptors in the CNS are linked with GABA receptors as a complex.
• Diazepam by binding to the benzodiazepine receptors results in activation of the GABA-benzodiazepine receptor complex, resulting in inhibition of nerve impulses, overall depression of brain and spinal cord.
• Thus, Diazepam helps to promote muscle relaxation, reduce anxiety, control of convulsions and promote sleep.

Dosage

• Diazepam is administered orally, rectally, and parenterally with the risk of dependence very much influencing the dose and duration of treatment.
• Courses of treatment should be short, not normally exceeding 4 weeks, with diazepam being withdrawal gradually.
• Elderly and debilitated patients should be given not more than one-half the usual adult dose

Anxiety	By mouth ADULT: 2 mg three times a day, then increased if necessary, to 15 – 30 mg daily in divided doses. ELDERLY: 1 mg three times a day, then increased if necessary to 7.5 – 15 mg daily in divided doses. Debilitated patients: use elderly dose
Insomnia associated with anxiety	By mouth ADULT: 5 – 15mg daily, to be taken at bedtime
For premedicationbefore general anaesthesia	By mouth ADULT: 5 – 10mg, to be given 1-2 hours before procedure ELDERLY: 2.5 – 5 mg, to be given 1-2 hours before procedure Debilitated patients: use elderly dose
For sedation during minor surgery	By mouth ADULT: Up to 20mg, to be given 1-2 hours before procedure
Status epilepticus Febrile convulsions Convulsions due to poisoning	By rectum CHILD 1 month – 1 years: 5 mg, then 5 mg after 10 minutes if required. CHILD 2 – 11 years: 5 – 10 mg, the 5 – 10 mg after 10 minutes if required. CHILD 12 – 17 years: 10 – 20 mg, then 10 – 20 mg after 10 minutes if required ADULT: 10 – 20 mg, then 10 – 20 mg after 10 – 15 minutes if required ELDERLY: 10mg, then 10 mg after 10 – 15 minutes if required
Dyspnoea associated with anxiety in palliative care	By mouth ADULTS: 5 – 10mg daily
Pain of muscle spasm in palliative care	By mouth ADULTS: 5 – 10mg daily
Muscle spasm	By mouth ADULTS: 2 – 15mg daily in divided doses, then increased if necessary to 60 mg daily.
Alcohol withdrawal syndrome	By mouth ADULTS: 5 to 20 mg, repeated if necessary after 2 to 4 hours; Or 10 mg three or four times on the first day, reducing to 5 mg three or four times daily as required.

Diazepam is rarely used for the long-term treatment of epilepsy because tolerance to its anticonvulsant effects usually develops within 6 to 12 months of treatment. Effectively rendering it useless for that purpose.

Side Effects

Sedative drugs, including alprazolam, have been associated with an increased risk of death.

Possible side effects include:

Very common (>10% of incidence) or Common(1-10% of incidence)	Shakiness and unsteady walk (especially in the elderly) Trembling, and other problems with muscle control or coordination Confusion (especially in the elderly) Amnesia Drowsiness the next day sedation Muscle weakness Paradoxical increase in aggression
Infrequent (0.1 -1% of incidence)	Dysarthria Gastro-intestinal disturbances Gynaecomastia Low blood pressure Incontinence Urinary retention Slurred speech Tremor Vertigo Visual disturbances
Rare (<0.1% of incidence)	Apnoea Blood disorders Jaundice Respiratory depression hypersensitivity reactions suicidal ideation

Overdosage can produce CNS depression and coma.

Paradoxical reactions (the opposite of what is to be expected) may occur. Symptoms include

• aggression, rage
• mania, agitation, and restlessness
• hallucinations, inappropriate behavior
• twitches and tremor

Pharmacokinetics

Oral bioavailability	Diazepam is well absorbed after oral doses.
Onset of action	Peak plasma concentrations occur between 30 and 90 minutes after an oral dose; and after 10 to 30 minutes when given as a rectal solution.
Metabolism	Diazepam is metabolized in the liver by the cytochrome P450 enzyme system. It has several active metabolites. Because of these active metabolites, the serum diazepam levels alone are not useful in predicting the effects of the drug.
Elimination half-life	Diazepam is excreted in the urine. The half-life of diazepam in general is 30 – 56 hours. Diazepam has a biphasic half-life of about 1 to 2 days, and 2 to 5 days for its principal active metabolite. The elimination half-life of diazepam and also the active metabolite increases significantly in the elderly, which may result in prolonged action and accumulation of the drug in the body.

Drug Management

Monitoring

• Blood pressure, pulse and respiratory rate are recommended
• Elderly may be sensitivity to diazepam’s effects. Impairment of memory, cognitive function, and psychomotor performance and behavior disinhibition may be common. Long-term use commonly exacerbates underlying dementia in elderly patients.
• Diazepam may make elderly patients feel dizzy, increasing risk of falls, so fall prevention is needed
• Some patients develop blood dyscrasias, and have raised liver enzymes, so periodic blood counts and liver function tests are recommended
• changes in mood, the development or worsening depression, and/or any thoughts or behaviour of suicide.

Dependence and Withdrawal

• One-third of individuals treated with benzodiazepines for longer than 4 weeks develop a dependence on the drug and experience a withdrawal syndrome on cessation.
• Withdrawal symptoms can range from insomnia and anxiety to more serious symptoms, including seizures and psychosis.
• Diazepam should therefore be withdrawn by tapering the dose to minimize occurrence of withdrawal symptoms.
• Tolerance develops to the anticonvulsant effects of diazepam.

Drug interaction

Medicines that interact with diazepam may either

• Decrease its effect
• Affect how long it works for
• Increase side effects

Common medications that may interact with diazepam include:

Drugs given with diazepam	Potential Effect
Alcohol, Hypnotics / sedative (e.g. barbiturates) Antidepressants (e.g. fluoxetine, amitriptyline) Sedative histamines (e.g. promethazine) Antipsychotic (e.g. chlorpromazine, clozapine)	May worsens the side effects such as drowsiness , dizziness and respiratory depression
Cimetidine Omeprazole Oxcarbazepine, Topiramate, Valproate Ketoconazole Itraconazole Isoniazid Erythromycin, Ciprofloxacin Propranolol Fluoxetine	Prolong the action of diazepam by inhibiting its elimination
Alcohol	May cause a synergistic enhancement of the hypotensive effect of diazepam and alcohol
Oral contraceptives	Oral contraceptives significant decrease the elimination of diazepam, so prolong the action of diazepam
Rifampicin Phenytoin Carbamazepine Phenobarbitone	All these drugs increase the metabolism of diazepam, thus decreasing drug levels and effects
Steroid (e.g. Dexamethasone) St John’s wort	Increase the metabolism of diazepam, thus decreasing diazepam plasma levels and effects
Theophylline	May inhibit the action of diazepam
Levodopa (e.g. Sinemet)	Diazepam may block the action of levodopa used in the treatment of Parkinson’s disease.
Foods that acidify the urine Food that alkalinize the urine	Can lead to faster absorption and elimination of diazepam, reducing drug levels and effects. Can lead to slower absorption and elimination of diazepam, increasing the diazepam plasma levels and effects.

Caution

• particular care in pregnancy,
• elderly, due to increased susceptibility to side-effects, especially loss of coordination and drowsiness
• in patients with hepatic or renal impairment, who may require reduced doses
• people with history of alcohol dependence or abuse
• people with history of drug dependence or abuse
• people with psychiatric disorders
• avoid prolonged use and abrupt withdrawal thereafter

Contra-indications

Use of diazepam should be avoided, when possible, in individuals with:

• severe hepatic impairment
• sleep apnoea
• chronic obstructive airways disease (COPD)
• Myasthenia gravis
• Acute narrow-angle glaucoma
• Chronic schizophrenia

Hepatic impairment

• Start with smaller initial doses or reduce dose.
• Can precipitate coma.
• Avoid in severe impairment.

Renal impairment

• Start with small doses in severe impairment.

Pregnancy

Possible adverse effects of use of benzodiazepines such as diazepam during pregnancy include: miscarriage, malformation, intrauterine growth retardation, and function deficits.

Breast-feeding

Use during breast feeding is not recommended.

Driving and skilled tasks

May impair judgment and increase reaction time, and so affect ability to drive or operate machinery. Patients should be warned not to operate dangerous machinery or motor vehicles until it is known that they do not become drowsy from diazepam therapy.

FAQ

How should I take the tablet?

May be taken with or without food. Swallow whole with a glass of water.

What should I avoid while taking?

Do not eat grapefruit or drink grapefruit juice as it may increase blood levels of diazepam.

Avoid drinking alcohol while taking diazepam because it may enhance the side effects of sedation and respiratory depression.

Avoid driving or hazardous activity until you know how diazepam will affect you.

What happen if I overdose?

Contact your primary care doctor. If emergency situation, call 999

What happen if I miss a dose?

Take it as soon as you remember. If it is near the time of the next dose, skip the missed dose. Take your next dose at the regular time. Do not double the dose to catch up.