Diazepam

Diazepam , first marketed as Valium by Hoffmann-La Roche, is a benzodiazepine derivative drug.

It possesses anxiolytic, anticonvulsant, sedative, skeletal muscle relaxant and amnestic properties. It is commonly used for treating anxiety, insomnia, seizures, alcohol withdrawal, and muscle spasms. It may also be used before certain medical procedures (such as endoscopies) to reduce tension and anxiety, and in some surgical procedures to induce amnesia.

Diazepam is a core medicine in the World Health Organization's "Essential Drugs List", which is a list of minimum medical needs for a basic health care system.[3] Diazepam is used to treat a wide range of conditions and has been one of the most frequently prescribed medications in the world for the past 40 years. It was invented by Dr. Leo Sternbach.

History

Diazepam was the second benzodiazepine to be invented by Sternbach of Hoffmann-La Roche, and was approved for use in 1963. It is two and a half times more potent than its predecessor, chlordiazepoxide, which it quickly surpassed in terms of sales. After this initial success, other pharmaceutical companies began to introduce other benzodiazepine derivatives.

The benzodiazepines gained popularity among medical professionals as an improvement upon barbiturates, which have a comparatively narrow therapeutic index, and are far more sedating at therapeutic doses. The benzodiazepines are also far less dangerous; death rarely results from diazepam overdose, except in cases where it is consumed with large amounts of other depressants (such as alcohol or other sedatives).

Diazepam was the top-selling pharmaceutical in the United States from 1969 to 1982, with peak sales in 1978 of 2.3 billion tablets. Diazepam along with oxazepam, nitrazepam and temazepam represent 82% of the benzodiazepine market in Australia. While psychiatrists continue to prescribe diazepam for the short-term relief of anxiety, neurology has taken the lead in prescribing diazepam for the palliative treatment of certain types of epilepsy and spastic activity, e.g., forms of paresis. It is also the first line of defense for a rare disorder called stiff-person syndrome.

Diazepam is also found in nature. Several plants, such as potato and wheat, contain trace amounts of naturally occurring diazepam and other benzodiazepines.

Physical properties

Diazepam occurs as solid white or yellow crystals and has a melting point of 131.5 to 134.5 °C. It is odorless, and has a slightly bitter taste. The British Pharmacopoeia lists diazepam as being very slightly soluble in water, soluble in alcohol and freely soluble in chloroform. The United States Pharmacopoeia lists diazepam as soluble 1 in 16 of ethyl alcohol, 1 in 2 of chloroform, 1 in 39 of ether, and practically insoluble in water. The pH of diazepam is neutral (i.e. pH = 7). Diazepam has a shelf-life of 5 years for oral tablets and 3 years for IV/IM solution. Diazepam is structurally related to quinazolines and is a hapten.

Diazepam should be stored at room temperature (15°-30°C). The solution for parenteral injection should be protected from light and kept from freezing. The oral forms should be stored in air-tight containers and protected from light.

Diazepam can absorb into plastic, and therefore diazepam solution is not stored in plastic bottles or syringes. It can absorb into plastic bags and tubing used for intravenous infusions. Absorption appears to be dependent on several factors such as temperature, concentration, flow rates and tube length. Diazepam should not be administered if a precipitate has formed and will not dissolve.

Pharmacology

Diazepam is a "classical" benzodiazepine, other classical benzodiazepines include; clonazepam, lorazepam, oxazepam, nitrazepam, flurazepam, bromazepam and clorazepate. Diazepam and other benzodiazepines may influence neurosteroid metabolism and progesterone levels which in turn may adversely influence the functions of the brain and reproductive system.

The pharmacological actions of benzodiazepines at the GABAa receptor are similar to those of neurosteroids. Neuroactive steroids are positive allosteric modulators of the GABAa receptor, enhancing GABA function. Many benzodiazepines (diazepam, medazepam, estazolam, flunitrazepam and nitrazepam) potently inhibit the enzymes involved in the metabolism of neurosteroids. Long-term administration of benzodiazepines may influence the concentrations of endogenous neurosteroids, and thereby would modulate the emotional state. Factors which affect benzodiazepines ability to alter neurosteroid levels depend on the molecular make up of the individual benzodiazepine molecule.

Presence of a substituent at N1 position of the diazepine ring and/or the chloro or nitro group at position 7 of the benzene ring contribute to potent inhibition of the isoenzymes, and in turn a bromo group at position 7 (for bromazepam) and additional substituents (3-hydroxy group for oxazepam and tetrahydroxazole ring for cloxazolam and oxazolam) decrease the inhibitory potency of benzodiazepines on neurosteroids.

Diazepam binds with high affinity to glial cells.

Diazepam is a potent inducer of melanogenesis in melanoma cells via modulating cell differentiation. Diazepam at high doses has been found to decrease histamine turnover via diazepam's action at the benzodiazepine-GABA receptor complex. Diazepam also decreases prolactin release. Diazepam has an inhibitory effect on plasma cholinesterase of 60--90 per cent.

Mechanism of action

Diazepam is a benzodiazepine that binds to a specific subunit on the GABAA receptor at a site that is distinct from the binding site of the endogenous GABA molecule.[19][20]The GABAA receptor is an inhibitory channel which, when activated, decreases neurologic activity.
Due to the role of diazepam as a positive allosteric modulator of GABA, when it binds to benzodiazepine receptors it causes inhibitory effects. This arises from the hyperpolarization of the post-synaptic membrane, due to the control exerted over negative chloride ions by GABAA receptors.

Benzodiazepines including diazepam however, do not have any affect on the levels of GABA in the brain.

Diazepam appears to act on areas of the limbic system, thalamus and hypothalamus, inducing anxiolytic effects. Its actions are due to the enhancement of GABA activity. Benzodiazepine drugs including diazepam increase the inhibitory processes in the cerebral cortex.

The anticonvulsant properties of diazepam and other benzodiazepines may be in part or entirely due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors. Sustained repetitive firing seems to be limited by benzodiazepines effect of slowing recovery of sodium channels from inactivation.

The muscle relaxant properties of diazepam are produced via inhibition of polysynaptic pathways in the spinal cord.

Pharmacokinetics

Diazepam can be administered orally, intravenously, intramuscularly, or as a suppository.When diazepam is administered orally, it is rapidly absorbed and has a fast onset of action. The onset of action is 1-5 minutes for IV administration and 15-30 minutes for IM administration. The duration of diazepam's peak pharmacological effects is 15 minutes to 1 hour for both routes of administration.

Peak plasma levels are achieved 30 minutes to 2 hours after oral administration. When diazepam is administered as an intramuscular injection, absorption is slow, erratic and incomplete.

Diazepam is highly lipid-soluble, and is widely distributed throughout the body after administration. It easily crosses both the blood-brain barrier and the placenta, and is excreted into breast milk. After absorption, diazepam is redistributed into muscle and adipose tissue. Continual daily doses of diazepam will quickly build up to a high concentration in the body (mainly in adipose tissue), which will be far in excess of the actual dose for any given day.

There is preferential storage of diazepam in some organs including the heart. Absortion by any administered route and the risk of accumulation is significantly increased in the neonate and there is clinical justification to recommend the withdrawal of diazepam during pregnancy and breast feeding.

Diazepam is metabolised via oxidative pathways in the liver via the cytochrome P450 enzyme system. It has a biphasic half-life of 1-2 and 2-5 days, and has several pharmacologically active metabolites. The main active metabolite of diazepam is desmethyldiazepam (also known as nordazepam or nordiazepam). Diazepam's other active metabolites include temazepam and oxazepam. These metabolites are conjugated with glucuronide, and are excreted primarily in the urine. Because of these active metabolites, the serum values of diazepam alone are not useful in predicting the effects of the drug.

Diazepam has a half-life (t1/2α) of 20-50 hours, and desmethyldiazepam has a half-life of 30-200 hours and is considered to be a long acting benzodiazepine.Most of the drug is metabolised; very little diazepam is excreted unchanged.

In humans, the protein binding of diazepam is around 98.5%.The elimination half life of diazepam and also the active metabolite desmethyldiazepam increases significantly in the elderly which may result in prolonged action as well as accumulation of the drug during repeated administration.

Indications

Diazepam is mainly used to treat anxiety, insomnia, and symptoms of acute alcohol or opiate withdrawal. It is also used as a premedication for inducing sedation, anxiolysis or amnesia prior to certain medical procedures (e.g. endoscopy).

Diazepam is rarely used for the long-term treatment of epilepsy. This is due to the fact that tolerance to the anticonvulsant effects of diazepam usually develops within 6 to 12 months of treatment, effectively rendering it useless for this purpose and also due to side effects - in particular sedation.

Diazepam has a broad spectrum of indications (most of which are off-label), including:
Treatment of anxiety, panic attacks, and states of agitation
Treatment of status epilepticus, adjunctive treatment of other forms of epilepsy
Treatment of the symptoms of alcohol and opiate withdrawal
Short-term treatment of insomnia
Treatment of tetanus, together with other measures of intensive-treatment
Initial management of mania, together with firstline drugs like lithium, valproate or other antipsychotics[citation needed]
Adjunctive treatment of painful muscle conditions
Adjunctive treatment of spastic muscular paresis (para-/tetraplegia) caused by cerebral or spinal cord conditions such as stroke, multiple sclerosis, spinal cord injury (long-term treatment is coupled with other rehabilitative measures)
Palliative treatment of stiff person syndrome
Used to alleviate the symptoms of Lesch-Nyhan Syndrome
Pre-/postoperative sedation, anxiolysis and/or amnesia (e.g. before endoscopic or surgical procedures)
Treatment of overdosage with hallucinogens or CNS stimulants
Adjunctive treatment of drug-induced seizures, resulting from exposure to sarin, VX, soman (or other organophosphate poisons; See CANA), lindane, chloroquine, physostigmine, or pyrethroids
Emergency treatment of eclampsia, along with IV magnesium sulfate
Prophylactic treatment of oxygen toxicity during hyperbaric oxygen therapy.
Used in the treatment for irritable bowel syndrome.
Used to treat pain resulting from muscle spasms caused by various spastic dystonias, including blepharospasm, spasmodic dysphonia and Meige's Syndrome.

Veterinary uses

Diazepam is used as a short term sedative and anxiolytic for cats and dogs. It is also used for short-term treatment of seizures in dogs and short-term and long-term treatment of seizures in cats. For emergent treatment of seizures, the typical dose is 0.5 mg/kg intravenously or 1-2 mg/kg per rectum of the injectable solution.

Diazepam is also used as a muscle relaxant for horses, to be given intravenously, the usual dose is 0.02 - 0.1 mg/kg in conjunction with or just after induction of general anesthesia.

Judicial Executions

The State of California offers Diazepam to condemned inmates as a pre-execution sedative.

Dosage

Dosages should be determined on an individual basis, depending upon the condition to be treated, the severity of symptoms, the body weight of the patient, and any comorbid conditions the patient may have.

Typical dosages for healthy adults range from 2 mg per dose to 10 mg per dose taken 2 to 4 times per day, depending on such factors as body weight and condition being treated. For the elderly or people with liver disorders, initial dose is at the low end of the range, with the dose being increased as required.

Trade names

Valium® tablets in USA and many other countries;
Valium® capsules in Italy, Spain;
Novodipam® in Canada;
Relanium® in Poland;
Seduxen® in Hungary, Russia;
Diazepam-Desitin® rectal solution in Hungary, and other European countries;
Diazepam-Intensol®;
Valrelease®
Diapam® in Finland
Stesolid® Sweden, Iceland
Anxicalm® Ireland

Availability

Diazepam is supplied in the following forms:
For oral administration:
Tablets - 2 mg, 5 mg, 10 mg. Generic versions available.
Capsules, time-release - 15mg (marketed by Roche as Valrelease®)
Liquid solution - 1 mg/ml in 500 ml containers and unit-dose (5 mg & 10 mg); 5 mg/ml in 30 ml dropper bottle (marketed by Roxane as Diazepam Intensol®)

For parenteral administration:

Solution for IV/IM injection - 5 mg/ml. 2 ml ampoules and syringes; 1 ml, 2 ml, 10 ml vials; 2 ml Tel-E-Ject; also contains 40% propylene glycol, 10% ethyl alcohol, 5% sodium benzoate and benzoic acid as buffers, and 1.5% benzyl alcohol as a preservative.

Notice : IM injection is largely less effective as the drug is injected into a tetanic muscle with compressed muscular veins . This does not allow the drug to reach the circulation rapidly.
Seduxen (Diazepam, in Hungary, Russia, Poland, and other Eastern-European countries) is supplied in the following forms:

For oral administration:

Tablets 5mg
Injection 5 mg/ml for intravenous, intramuscular or subcutaneous usage

For parenteral administration:

Solution for IV/IM injection - 5 mg/ml. 2 ml ampoules and syringes; 1 ml, 2 ml, 10 ml vials; 2 ml Tel-E-Ject; also contains 40% propylene glycol, 10% ethyl alcohol, 5% sodium benzoate and benzoic acid as buffers, and 1.5% benzyl alcohol as a preservative.
Notice : IM injection is largely less effective as the drug is injected into a tetanic muscle with compressed muscular veins . This does not allow the drug to reach the circulation rapidly.

For rectal administration:

Solution
Suppositories - 5mg and 10mg
Rectal tubes
For inhalation administration:This method uses heating diazepam to form a vapor later producing an aerosol. This allows the drug to be passed through an inhalation route during an inhalation therapy. Provided in doses 2mg-20mg either in a single inhalation or multiple small inhalations

Side effects

Diazepam has a range of side effects which are common to most benzodiazepines. Most common side effects include:
Somnolence
Suppression of REM sleep
Addiction
Impaired motor function
Impaired coordination
Impaired balance
Dizziness and nausea
Depression
Impaired learning
Anterograde amnesia (especially pronounced in higher doses)
Cognitive deficits
Reflex tachycardia

Rare paradoxical side effects can include: nervousness, irritability, insomnia, muscle cramps, and in extreme cases, rage, and violence. If these side effects are present, diazepam treatment should be immediately terminated.

Benzodiazepines such as diazepam impair learning and memory via their action on benzodiazepine receptors which causes a dysfunction in the cholinergic neuronal system.
Diazepam may impair the ability to drive vehicles or operate machinery. The impairment is worsened by consumption of alcohol, because both act as central nervous system depressants.

During the course of therapy, tolerance to the sedative effects usually develops, but not to the anxiolytic and myorelaxant effects.

Patients with severe attacks of apnea during sleep may suffer respiratory depression (hypoventilation) leading to respiratory arrest and death.
Organic changes such as leukopenia and liver-damage of the cholostatic type with or without jaundice (icterus) have been observed in a few cases.[citation needed]
Diazepam in doses of 5 mg or more causes significant deterioration in vigilance performance combined with increased feelings of sleepiness.

Interactions

If diazepam is to be administered concomitantly with other drugs, attention should be paid to the possible pharmacological interactions. Particular care should be taken with drugs that enhance the effects of diazepam, such as barbiturates, phenothiazines, narcotics and antidepressants.

Diazepam does not increase or decrease hepatic enzyme activity, and does not alter the metabolism of other compounds. There is no evidence that would suggest diazepam alters its own metabolism with chronic administration.

Agents which have an effect on hepatic cytochrome P450 pathways or conjugation can alter the rate of diazepam metabolism. These interactions would be expected to be most significant with long-term diazepam therapy, and their clinical significance is variable.

Diazepam increases the central depressive effects of alcohol, other hypnotics/sedatives (e.g. barbiturates), narcotics, and other muscle relaxants. The euphoriant effects of opioids may be increased, leading to increased risk of psychological dependence.

Cimetidine, omeprazole, ketoconazole, itraconazole, disulfiram, fluvoxamine, isoniazid, erythromycin, probenecid, propranolol, imipramine, ciprofloxacin, fluoxetine and valproic acid prolong the action of diazepam by inhibiting its elimination.

Alcohol (ethanol) in combination with diazepam may cause a synergistic enhancement of the hypotensive properties of benzodiazepines and alcohol.

Oral contraceptives ("the pill") significantly decrease the elimination of desmethyldiazepam, a major metabolite of diazepam.

Rifampin, phenytoin, carbamazepine and phenobarbital increase the metabolism of diazepam, thus decreasing drug levels and effects.

Diazepam increases the serum levels of phenobarbital.
Nefazodone can cause increased blood levels of benzodiazepines.
Cisapride may enhance the absorption, and therefore the sedative activity, of diazepam.
Small doses of theophylline may inhibit the action of diazepam.

Diazepam may block the action of levodopa (used in the treatment of Parkinson's Disease).
Diazepam may alter digoxin serum concentrations.
Other drugs that may have interactions with diazepam include: Antipsychotics (e.g. chlorpromazine), MAO inhibitors, ranitidine.

Smoking tobacco can enhance the elimination of diazepam and decrease its action.
Because it acts on the GABA receptor the herb Valerian may produce an adverse effect.
Foods that acidify the urine can lead to faster absorption and elimination of diazepam, reducing drug levels and activity.

Foods that alkalinize the urine can lead to slower absorption and elimination of diazepam, increasing drug levels and activity.
There are conflicting reports as to whether food in general has any effects on the absorption and activity of orally administered diazepam.

Contraindications

Use of diazepam should be avoided, when possible, in individuals with the following conditions:
Ataxia
Severe hypoventilation
Acute narrow-angle glaucoma
Severe hepatic deficiencies (hepatitis and liver cirrhosis decrease elimination by a factor of 2)
Severe renal deficiencies (e.g. patients on dialysis)
Severe sleep apnea
Severe depression, particularly when accompanied by suicidal tendencies
Acute intoxication with alcohol, narcotics, or other psychoactive substances (with the exception of some hallucinogens, where it is occasionally used as a treatment for overdose)
Myasthenia gravis
Hypersensitivity or allergy to any drug in the benzodiazepine class

Special caution needed

Pediatric patients
Less than 18 years of age - Treatment usually not indicated, except treatment of epilepsy, and pre-/postoperative treatment. The smallest possible effective dose should be used for this group of patients.

Under 6 months of age - Safety and effectiveness have not been established; diazepam should not be given to individuals in this age group.

Elderly and very ill patients - Possibility that apnea and/or cardiac arrest may occur. Concomitant use of other central nervous system depressants increases this risk. The smallest possible effective dose should be used for this group of patients.

Diazepam may also be dangerous in geriatric patients due to a significant increased risk of falls.
I.V. or I.M. injections in hypotensive individuals or those in shock should be administered carefully and vital signs should be monitored.

Benzodiazepines such as diazepam are lipophilic and rapidly penetrate membranes and therefore rapidly crosses over into the placenta with significant uptake of the drug. Use of benzodiazepines including diazepam in late pregnancy, especially high doses, may result in floppy infant syndrome.

Dependence

Diazepam as with other benzodiazepine drugs can cause physical dependence, addiction and what is known as the benzodiazepine withdrawal syndrome. Withdrawal from diazepam or other benzodiazepines often leads to withdrawal symptoms which are similar to those seen during alcohol and barbiturate withdrawal.

The higher the dose and the longer the drug is taken for the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can occur from standard dosages and also after short term use. Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regime.

It has been shown in a clinical study that 100% of patients on low dose diazepam therapy long term are physically dependent on their medication. Increased ratings of dizziness, blurred vision, heart pounding, feelings of unreality, pins and needles, nausea, sweatiness, noises louder than usual, jitteriness, things moving, sensitivity to touch and panic attacks may be experienced as withdrawal symptoms in low therapeutic dose long term users of diazepam when discontinuing their diazepam medication.

Rebound anxiety, more severe than baseline anxiety, is also a common withdrawal symptom when discontinuing diazepam or other benzodiazepines. Diazepam is therefore only recommended for short term therapy at the lowest possible dose due to risks of severe withdrawal problems from low doses even after gradual reduction.

There is a significant risk of pharmacological dependence on diazepam and patients experiencing the benzodiazepine withdrawal syndrome if it is taken for 6 weeks or longer.
In humans tolerance to the anticonvulsant effects of diazepam occurs frequently.

[edit] Patients at a high risk for abuse, dependence, tolerance, or addiction
Diazepam can lead to physiological tolerance, and psychological and/or physical dependence.

At a particularly high risk for diazepam misuse, abuse, or dependence are:
Patients with a history of alcohol or drug abuse or dependence
Patients with severe personality disorders, such as Borderline Personality Disorder
Patients with an Anxiety Disorder
Patients from the aforementioned groups should be monitored very closely during therapy for signs of abuse and development of dependence. Discontinue therapy if any of these signs are noted. Long-term therapy in these patients is not recommended.

The American Society of Addiction Medicine has policy indicating that patients with addictive disease should not be prescribed benzodiazepines such as diazepam.[citation needed]

Pregnancy

There is inconclusive evidence that diazepam if taken early in pregnancy may result in reduced IQ, neurodevelopmental problems, physical malformations in cardiac or facial structure as well as other malformations in some newborns, however the data is inconclusive.

Diazepam when taken during late in pregnancy, the third trimester, causes a definite risk of a severe benzodiazepine withdrawal syndrome in the neonate with symptoms including hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Floppy infant syndrome and sedation in the newborn may also occur. Symptoms of floppy infant syndrome and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth.

Overdose

An individual who has consumed too much diazepam will display one or more of the following symptoms:

Drowsiness
Mental confusion
Hypotension
Impaired motor functions
Impaired reflexes
Impaired coordination
Impaired balance
Dizziness
Coma

Although not usually fatal when taken alone, a diazepam overdose is considered a medical emergency and generally requires the immediate attention of medical personnel. The antidote for an overdose of diazepam (or any other benzodiazepine) is flumazenil (Anexate®). This drug is only used in cases with severe respiratory depression or cardiovascular complications. Because flumazenil is a short-acting drug and the effects of diazepam can last for days, several doses of flumazenil may be necessary. Artificial respiration and stabilization of cardiovascular functions may also be necessary. Although not routinely indicated, activated charcoal can be used for decontamination of the stomach following a diazepam overdose. Emesis is contraindicated. Dialysis is minimally effective. Hypotension may be treated with levarterenol or metaraminol.

The oral LD50 (lethal dose in 50% of the population) of diazepam is 720mg/kg in mice and 1240mg/kg in rats. D. J. Greenblatt and colleagues reported in 1978 on two patients who had taken 500 and 2000 mg of diazepam, respectively, went into moderately deep comas, and were discharged within 48 hours without having experienced important complications in spite of having high concentrations of diazepam and its metabolites—desmethyldiazepam, oxazepam, and temazepam—according to samples taken in the hospital and as follow-up.
Overdoses of diazepam with alcohol, opiates and/or other depressants may be fatal.

Recreational and illicit use

Diazepam is a drug of potential dependence and addiction. Between 50 and 64% of rats will self administer diazepam. Benzodiazepines including diazepam in animal studies have been shown to increase reward seeking behaviours by increasing impulsivity which may suggest an increased risk of addictive behavioural patterns with usage of diazepam or other benzodiazepines. Diazepam is often found as an adulterant in heroin. This may be because diazepam greatly amplifies the effects of opioids.

Sometimes diazepam is used by stimulant users to 'come down' and sleep and to help control the urge to binge.
Benzodiazepines, including diazepam, temazepam, nitrazepam and flunitrazepam account for the largest volume of forged drug prescriptions in Sweden, a total of 52% of drug forgeries being for benzodiazepines.

Diazepam was detected in 26% of cases of people suspected of driving under the influence of drugs in Sweden and its active metabolite nordazepam was detected in 28% of cases. Other benzodiazepines and zolpidem and zopiclone also were found in high numbers. Many drivers had blood levels far exceeding the therapeutic dose range suggesting a high degree of abuse potential for benzodiazepines and zolpidem and zopiclone.[78] In Northern Ireland in cases where drugs were detected in samples from impaired drivers who were not impaired by alcohol, benzodiazepines were found to be present in 87% of cases. Diazepam was the most commonly detected benzodiazepine.

It is sometimes referred to by street names, including 'blues', 'mother's little helper', 'diazies', 'drunk pills', 'vals', 'V', and occasionally 'ludes', mistaken for Quaaludes. As well as less specific street terms, 'candy' (pills), 'benzos' (benzodiazepines), or downers (depressants).

Legal status

Internationally, diazepam is a Schedule IV drug under the Convention on Psychotropic Substances. In the UK, it is classified as a Class C drug.

Toxicity

Laboratory tests assessing the toxicity of diazepam, nitrazepam and chlordiazepoxide on mice spermatozoa found that diazepam produced toxicities in sperm including abnormalities involving both the shape and size of the sperm head. Nitrazepam however caused more profound abnormalities than diazepam.

Source : www.wikipedia.org/