A elaborate pharmacological S.W.O.T analysis of the hypnotic Triazolam.

Triazolam ( trade name name Halcion ) is thegeneric name of a sleep promoting drug used in patients that suffer frominsomnia. It is a member of the benzodiazepine ( BZPs ) household of drugs. Thisfamily includes amongst others ; Xanax ( Xanax ) , diazepam ( Valium ) , flurazepam ( Dalmane ) , lorazepam ( Ativan ) clonazepam ( Klonopin ) ( FDA,2003 ) .

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Benzodiazepines werefirst used 40 old ages ago and they were seen to be a discovery in the field, holding fewer drawbacks than its predecessors. BZPs have a satisfactorily widesafety border for overdoses, nominal pharmacokinetic drug interactions, and a goodlevel of tolerability, while keeping effectivity for a wide scope ofconditions. Because of this, BZPs continue as widely prescribed drugs worldwide ( Janicak, 1997, Greenblatt, 2000 ) .

Existing utilizations of BZPs arediverse. Amongst the conditions treated are insomnia, passion, anxiousness upsets ( panic upset, generalized anxiousness, phobic disorder, anxiousness associated withobsessive compulsive upset ) , catatonia, and behavior control in psychoticpatients, neuroleptic-induced side effects including akathisia, musculus cramps, ictuss, and intoxicant backdown ( Wheatly, 1992 ) .

Anxiety is thought to be the underlyingcause of insomnia, a status where the encephalon is excessively active.Gamma-aminobutyric acid ( GABA ) , produced in the encephalon, is a substance whichinhibits nervousnesss and infinite activities of the encephalon. Triazolam and other BZPsaugment the effects of GABA and so cut down activity in the encephalon which promotessleep ( Greenblatt, 2000 and 2004 ) .

Triazolam was approved by the FDA in 1982. The merchandise licenses for Halcion inBritain were suspended in October 1991 ( FDA, 2003 ) .


The hypnoticpharmacokinetic profile of Halcion is really desirable. It has a really shortelimination half life, is quickly captive and peak plasma concentration ( C ( soap ) ) is reached in 1.0 to 1.5 hours following unwritten disposal ( Kales,1986 ) .

C ( soap ) and country underthe plasma-concentration curve ( AUC ) addition in proportion to the dosage, howeverthe clip to top out plasma concentration, riddance half life, and clearance areindependent of dosage. The riddance half life is 2.3 hours ( run 1.7 to 3.0hours ) ( Bernstein, 1995 ) .

Triazolam is metabolised bymeans of hepatic microsomal oxidization. The inactive, hydroxylated metabolitesare excreted chiefly in the piss as conjugated glucuronides. The two primarymetabolites account for about 80 % of the urinary elimination. Insistent administrationof Halcion over 7 yearss does non take to accretion and does non change therate of riddance ( Jonas, 1992 ) .

Pharmacokineticss in the aged

Peoples that are aged over 60 do notdemonstrate an altered riddance half life, though peak plasma concentrationsare significantly increased. The dynamicss of Halcion is significantlyprejudiced by age. Following individual unwritten doses of 0.125 milligrams and 0.25 milligram oftriazolam, C ( soap ) and AUC were significantly higher and clearancesignificantly lower in aged topics than in younger 1. Age, nevertheless, didnot influence the clip to top out plasma degrees and differences in eliminationhalf-life were bantam ( Greenblatt, 2004 ) .

S.W.O.T analysis


The effectivity of triazolamhas been verified in many surveies including Rickels et Al, ( 1998 ) who affirmed thattriazolam caused important and indistinguishable decrease of insomnia. Long found in1995 that in sleep research lab surveies of 1 to 21 yearss continuance, triazolamreduced sleep latency, increased continuance of slumber and decreased the figure ofawakenings.

Triazolam has a extremely advantageousclinical lineation ; it is really easy to present as it is available in oralcapsule. Patients are able to self-administer by and large with no jobs. It isfast moving, C ( soap ) being reached in every bit small as one hr. The eliminationhalf-life and elimination rate is highly fleet ; therefore it is removed fromthe system rapidly, bespeaking there is negligible residuary action in the organic structure ( Quarnstorm, 2004 ) .

Triazolam has a high selectivity forthe intellectual GABAA benzodiazepine ( BDZ ) receptor composite, nevertheless the binding is weak. This is of import because drugswith low selectivity have the ability to adhere to other receptors and perhapscause unwanted effects in other countries of the organic structure.

Cost is a factor which even thoughnot associated with safety of the drug, affects how frequently a clinicianprescribes. Triazolam is an effectual and cheap drug ; in 2005 the costfor a month ‘s supply of the drug in the USA costs $ 3 ( Oregan GUR, 2005 ) which is considerablecheaper than other comparable drugs.


The survey that Longperformed in 1995 highlighted the efficaciousness of Halcion but besides demonstratedits failings. He found that after 2 hebdomads of back-to-back nightlyadministration, the drug ‘s consequence on entire aftermath clip is diminished, and thevalues in the concluding tierce of the dark attack baseline. On the first orsecond dark after drug discontinuation, entire slumber, and proportion of timespent kiping often were significantly less, and sleep latency drasticallyincreased when evaluated against baseline darks, an consequence known as ” recoil ” insomnia.

The extent ofhypnotic consequence and presence of unwanted effects may be capable to the alpha ( distribution ) and beta ( riddance ) half-lives of Halcion. Triazolam has ashort half life which means, the drug and its metabolites will be excreted priorto consumption of the following dosage. Residual effects associated with sedation or CNSdepression are minimum or absent. During every night usage and for an extendedepisode, pharmacodynamic credence or version to some effects of triazolammay develop ( APA, 1990 ) .

The drug hasa really brief riddance half life ; therefore it is possible that a deficiencyin relation to the receptor site could take topographic point at some point in the intervalbetween each every night usage. This happening may account for the two clinicalfindings ; Increased wakefulness during the last tierce of the dark and theappearance of increased day-time anxiousness, which were reported after severalweeks of every night usage of Halcion.

Triazolam can contributeto the consequences other drugs demonstrate that inhibit activity in the encephalon. Thisincludes intoxicant, barbiturates, narcotics and some pharmaceutics antihistamines ( e.g. Benadryl ) . Uniting these drugs with Halcion may do utmost sedation.When employed for indicants other than insomnia, this sedation is frequently a drawbackand could put vulnerable patients such as the aged at hazard ( APA, 1990 ) .

Another undesirableeffect is that some drugs ( e.g. Sporanox, Erythrocin and fluconazole ) , and alsograpefruit juice ( Lilja, 2000 ) , can barricade the metamorphosis of Halcion from thebody. This raises Halcion degrees and besides causes inordinate sedation. At theopposite terminal of the spectrum, drugs such as Phenytoin and rifampin increasethe rate of riddance of Halcion from the organic structure and can originate a loss oftriazolam ‘s effectivity.

Memory jobs havebeen recognized in all BZPs and are particularly debatable with Halcion. Thisis potentially scaring to patients and there are several cases focusingon this in the USA, against clinicians who did non warn their patients of thispossibility ( Rothschild, 1992 ) .

When a drug interfereswith the usual inhibiting action of GABA within the cardinal nervous system, thiscan lead to uncontrolled fire of urges, ensuing in the flight fromhigher cortical control. This means that behaviour can be altered to a province ofdisinhibition. This can be a peculiar job with the usage of Halcion.

In the aged who aretaking BZPs, falls and ataxies are of a peculiar concern. Those takingtriazolam are 1.5-3 times more likely to endure a autumn.


There is really small inthe manner of chances for the development of Halcion. The degrees ofefficacy and selectivity that it demonstrated are ideal. It is besides inexpensive andeasy to present. Opportunities for advancement with this drug Centre around itspossible re-release to the worldwide market ( Berstein, 1995 ) .

In 1979, the safety of triazolamwas foremost queried when new wave der Kroef reported a syndrome that includeddepression, memory loss, hallucinations, and anxiousness with its usage. Many othersafety concerns followed this. In 1992 the Food and Drug Administration ( FDA ) decreasedthe dosage recommended in the labeling down to 0.25 milligram for grownups and 0.125 mgfor the geriatric population. These lower doses were non included in thestudies performed during the original FDA blessing procedure. The alteration raisesthe inquiry of if there is equal informations to back up the recommendation andwhether the minimal effectual dosage has been established.

To seek toanswer these dose-related efficaciousness inquiries and to measure the value of thedata the FDA based its determination that Halcion was effectual at the lower doseson, an rating and reanalysis of the information was performed utilizing a statisticalmethod different from that used by FDA, the study was inconclusive and needsfurther research. ( Marticello, 1992 ) ;

There is theprospect that Halcion could be a utile drug in other Fieldss. Other drugswhich have been found to be debatable in their original field have gone on tobe really successful in other countries. An illustration of this is thalidomide ; thecontroversy environing this drug has been good documented for its initial usein the 1940s and 1950s, used to bring around forenoon illness, but it is now apotential campaigner anti-cancer drug.


Triazolam ‘s safety has beenquestionable. In 1991, as a consequence of a US tribunal instance, the UK ‘s Committee onSafety of Medicines ( CSM ) became cognizant that in the merchandise licence applicationfor Halcion, there were a figure of skips of inauspicious events.

Surveies were conducted in US volunteersin 1972 utilizing a 1 milligram dosage of Halcion. Pharmacia & A ; Upjohn ( maker oftriazolam ) , provided the CSM with the original clinical record signifiers from thestudy for reappraisal. The CSM revaluation of this protocol and inauspicious drugreaction records from the UK and US led to the decision: “ . . . thattriazolam is associated with an unequal border of safety in relation to doseand that its hazards outweigh its benefits in relation to otherbenzodiazepines. ” ( CSM, 1992 )

An FDA memo from 1994 exposedthe fact that 30 per centum of the serious inauspicious drug reactions seen in thestudy topics had non been reported to the FDA before the drug ‘s blessing in theUS. Selling blessing for Halcion was in the terminal, withdrawn in the UK, Brazil, Argentina, Norway, and Denmark.

There are risksassociated with:

Dependence: after anumber of hebdomads of usage, physical dependence can originate and often becomes obviouswhen trying to stop drawn-out periods of usage. With rapid backdown, patientssuffer a fleet backsliding of original symptoms frequently with hyperbolic strength ( recoil ) and accompanied by new symptoms ( backdown ) ( Jonas, 1992 ) .

The CSM inthe UK concluded that the hazards linked with Halcion usage prevail over thebenefits and that this agent should be avoided, peculiarly in the aged ( CSM, 1992 ) .


Triazolam has achievednotoriety because of studies that it causes behavioural perturbations, includingpsychosis and violent behaviour ( Wheatley, 1992 ) . However, the doses involved ( over 1 milligrams ) were twice the usual upper limit dosage presently prescribed ( Kales,1986 ) . These effects remain controversial because two meta-analyses of studiescomparing Halcion with other benzodiazepines have failed to demo anydifference in behavioural effects ( Jonas, 1982, Kales, 1986 ) .

This was besides noted by Jonas in 1992. The efficaciousness, safety, and public presentation of Halcion was evaluated against other shorter-actinghypnotics moving on the GABA receptor ( zopiclone, zolpidem, Versed, brotizolam, Restoril, lormetazepam, and loprazolam ) .

Two wide findings cameforward. Exhilaration and force were non demonstrated for any of the hypnoticagents, including Halcion. These are by and large viewed as “ serious ” cardinal nervous system side effects. Extra cardinal nervous system sideeffects, e.g. depression and crossness, were demonstrated in equal numbersfor all the soporifics appraised.

Rebound insomnia, commonlyreported with most of these soporifics, was brief and non clinicallysignificant. Early forenoon insomnia was noted on one juncture and was notclinically important. In contrast to claims that Halcion is anxiogenic, anxiousness was non a big determination within the cohort.

Second, a notablecomparison was established among all the agents in footings of efficaciousness, sideeffects, and public presentation related effects. Claims have been made proposing differences ; rating of the survey did non show this. Therefore difference in chemicalstructures does non needfully foretell a difference in clinical profiles whendrugs portion a similar mechanism of action ( Jonas, 1992, Kamien, 1994 ) ) .

Triazolem remainslicensed in the USA. The American Public Health Research Group ( APHRG ) has saidthat Halcion is excessively unsafe to utilize and we advise anyone utilizing it to asktheir physician to assist them easy withdraw from the drug it is hooking orswitch to a safer sleeping pill.

The market, every bit good asthe U.K. authorities, has besides spoken aloud and clearly about the drug. Gross saless, measured by retail prescriptions filled per twelvemonth, have plummeted from a peak of11 million prescriptions a twelvemonth in 1988 to 1.8 million in 1996, a bead of 84 % ( Peart, 1998 ) .

Huge Numberss of studiespoint to the fact that Halcion is non a safe and effectual drug. Halcion isused chiefly to battle insomnia on a really short-run footing. When taken forover two hebdomads, Halcion normally loses its effectivity. There are a broad rangeof alternate drugs available to handle insomnia and anxiousness upsets which couldbe used in penchant to triazolem ( Kamien, 1994 ) .

Conversely, the drug ischeap and really effectual in the short term. More surveies are required todetermine its safety, both in the short and long term. There appears to be anequal sentiment for and against it. It is dubious that Halcion would begranted a licence today due to the negative findings in surveies and the hugedebate environing the drug, nevertheless if its safety could be eventually determinedthen it would be a utile agent. Its usage in other waies should besides beinvestigated before make up one’s minding the future destiny of the drug. Datas from the USAwould be a valuable plus in the drugs future as it is still widely used there ( Barbera, 2005 ) .


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