The advantages of oral triazolam sedation
Oral sedation with triazolam is simple to administer and, because of the nature of the drug, it is convenient and safe to use. Triazolam is readily available from any pharmacy and does not require any extra equipment to administer. Reports of adverse drug reactions are rare and tend to be relatively mild. A major plus for all oral sedatives is that it is not necessary to administer an injection or start an intravenous line. (The last thing most phobic patients need is a needle puncture before they are sedated.) Patients readily accept oral sedation, although recently some have declined triazolam because of the adverse press it has generated when used as a sleeping pill. Finally, oral sedation is relatively inexpensive for our patients.
Historically, we have used barbiturates and narcotics, both of which have significant effects on respiration and circulation. Diazepam has been used with good effects, but it is slow being absorbed and has a very long half-life. On the other hand, triazolam is a drug that has been around for some time but has been used primarily to aid sleep. In this context, it has received bad press because of side effects that have shown up in patients that use it over an extended period of time. It is the most commonly prescribed sleeping pill used in the US; 7.2 million prescriptions are written annually. It should be emphasized that triazolam is not approved by the FDA as a sedative for dental purposes.
Triazolam has the advantage of being absorbed rapidly, achieving peak blood levels in 1.3 hours; its half-life is 2-3 hours, much shorter than diazepam. In addition, it may be up to eight (8) times more effective as a hypnotic than diazepam. Yet, triazolam has very little effect on the circulatory or respiratory system. Several studies have shown no changes in blood pressure, pulse, or percentage of oxygen saturation and only a slight change in respiratory rate. It is metabolized in the liver by the P450 mixed function oxidase system on the smooth endoplasmic reticulum. It is excreted 90% in the urine, 9% in the faeces. Its metabolites are not sedative as is the case with diazepam. It does react adversely when taken with a popular antacid, Cimetidine (Tagamet), which inhibits the P450 system of the liver.
Structure-activity relationship The unique properties of triazolam are attributed to its chemical configuration. The nitrogen atom prevents it from being water soluble. Medazolam has a carbon in this position and thus is water soluble and suitable for IV administration. One chlorine atom is responsible for potency; without this chlorine it is one fifth as potent. Larger alkyl substitutions also decrease potency. The second chlorine is necessary for benzodiazepine action. Bromo and nitro substitution are only weakly anxiolytic. The nitro version is anticonvulsant as illustrated by clonazepam. The triazolo ring and attached methyl group are responsible for the rapid oxidation by the liver enzymes, resulting in a short elimination half life and conversion to metabolites that are rapidly excreted. The methyl group also makes more potent.
Triazolam reaches a rapid peak within 1.3 hours, faster in the elderly and in young women. This occurs more rapidly in daytime than at night, due to longer predose fasting period and is as much as 2 times quicker after a 12 hour fast. Eighty-five percent (85%) is absorbed into the blood stream, 15% passes through in the faeces. It is absorbed 28% faster if given sublingually where some of it is absorbed, but most of it is swallowed.
The distribution of triazolam shows no difference in obese and normal patients. It is 89% bound to plasma, 49% to serum proteins, crosses readily into the central nervous system because of high lipid solubility, and crosses the placental barrier and milk of rats.
Metabolism and Elimination
Triazolam is oxidized in the first pass in the liver by the cytochrome P450-mediated oxidatative system. There have been 6 metabolites identified. Alpha hydroxytriazolam and 4-hydroxytriazolam make up 69% and 11% of the metabolites, respectively. Alpha hydroxytriazolam is 50-100% of the pharmacological activity of triazolam. It is present in the plasma in only very low levels and that which is present is the conjugate form and not active. Triazolam has no active metabolites. Its half- life averages 1.2 to 3.3 hours, but slower at night. Half-life is longer in the elderly because of lower liver oxidizing capacity. There is no change with kidney dialysis but it is slower with cirrhosis. Ninety-one percent (91%) is eliminated in urine and 9% in faeces within 72 hours.
Cimethedine reduces the first pass liver clearance by decreased metabolism and reduction in hapatic blood flow due to decrease in cytochrome P450-mediated oxidatative system. The same effect occurs with erythromycin, isoniazid, an antitubercular agent and possibly some oral contraceptives.
Central Nervous System
All the benzodiazepines have clinically useful anti-anxiety, sedative-hypnotic, anticonvulsant and skeletal muscle relaxant properties. They all depress CNS to some degree, tending to be more anti-anxiety oriented as compared with barbiturates and other sedative-hypnotics. They depress the limbic system and areas of the brain associated with emotion and behavior, particularly the hippocampus and the amygdaloid nucleus.
The major effects are attributed to an interaction with the Gamma Amino Butyric Acid (GABA) receptor complex; it alters the chloride ion channels to increase the frequency of their opening. It potentiates GABA. It is now known that there are several GABA receptor sites. Thus, in the future we may have drugs more specific to anti-anxiety with fewer side effects. Benzodiazepines also interact with the glycine receptors, alter opiate peptide concentrations and 5-HT decreases, a precursor of Seratonin.
In normal therapeutic doses, the benzodiazepines cause few alterations in cardiac output or blood pressure when administered intravenously to healthy persons. Slightly greater than normal doses cause slight decreases in blood pressure, cardiac output, and stroke volume in normal subjects and patients with cardiac disease, but these changes are not usually clinically significant. Triazolam did not affect cardovascular dynamics in doses 4 to 8 times normal.
Benzodiazepines are respiratory depressants. However, given alone to a healthy patient they have little effect. They potentiate other CNS depressants. Medazolam is one that can cause respiratory depression and apnea. Triazolam did not depress respiratory response to CO2 in doses 4 to 8 times normal.
In rats, slightly reduced fertility occurred but the drug did not affect their postnatal development.
One method of measuring recovery is to have the patient stand with their eyes closed. Patients were normal after 3.5 hours with a .25 mg dose, after 5 hours with a 1. mg. dose, and after 7 hours with a 2. mg. dose. A visual coordination study (following a randomly moving dot with their finger) had patients back to normal after ingesting .25 mg in 5 hours and .5 mg in 11.5 hours. One study using .5 mg had an incident of side effects of 8% sleepiness and 4% headache, dizziness, neuritis, dry mouth.
Mechanisms of action
Benzodiazepines have two current hypotheses of receptor interaction - either a multi-receptor or a single receptor with multiple conformations. GABA (gamma-aminobutyric acid), an amino acid transmitter in the brain, has no known function besides serving as a neurotransmitter and occurs almost exclusively in the brain. GABA reduces the firing of neurons and is an inhibitory neurotransmitter. It is the transmitter at 25 to 40 percent of all synapses in the brain, thus, quantitatively, it may be the brain's predominant transmitter.
Diazepam relieves anxiety, but produces some drowsiness, which is tolerated after several weeks of use. Unfortunately, benzodiazepines are somewhat addicting, with withdrawal symptoms if dosage is stopped. The biggest advantage of the benzodiazepines is the fact that overdoses are rarely lethal. The dose necessary to create problems is many times the therapeutic dose. In this sense, they are among the safest drugs known.
How Benzodiazepines Act
It was established in the 1960's that benzodiazepines and many other sedatives act by affecting the synapse. Cross tolerances were shown with the barbiturates, meprobamate and alcohol. Benzodiazepines act at a different but closely related recognition site. Alcohol, barbiturates and meprobamate all act at the same site. These drugs, as opposed to the benzodiazepine drugs, all put animals to sleep with only modestly higher doses than are required for sedation. This is true in a number of other behavioral tests.
Receptor Sites It was shown that all these drugs interact with the neurotransmitter GABA. When GABA binds with a receptor site on the neurons, it slows the neuron's rate of firing. The GABA receptor is an integral membrane protein. It extends through the bilayered outer membrane of the postsynaptic neuron. GABA has two receptors designated GABA-A and GABA-B. The A receptor changes the ion permeability of the chloride-ion. The B receptor changes the ion permeability of the potassium-ion. In both instances, the effect is the same. Research in the early 60's showed that inhibitory effects of GABA were potentiated by alcohol, barbiturates, meprobamate and benzodiazepines.
In 1977 two groups showed the existence of specific benzodiazepine receptors in the brain. GABA has similar sites. Benzodiazepines only bind to the GABAs. If either is present, the other's binding ability is enhanced. It is assumed that either effects the shape of the binding site of the other. Both binding sites are on one large protein molecule. Thus, the effects of diazepam are explained by the increased activity of GABA.
The receptor sites are concentrated in parts of the brain that regulate emotional behavior. Within the limbic system, high concentrations are found in the Amygdala. A third receptor site has been shown to exist on the large protein. It is a sedative-convulsant site. This is the site of action of alcohol, barbiturates, and meprobamate and may be effected by drugs that cause convulsions. It was shown that all three sites interact with the other two sites. GABA inhibits synaptic transmission by widening the chloride-ion channels in the neuronal membrane. The receptor site looks much like eight long beads arranged side by side to form a tunnel. Each bead is a molecular helictical structure. Connecting the beads is a linear stretcher strung through the helictical beads which loops from bead to bead. Loops of this material form the A and B sites. It is through the resulting pores that chloride-ions enter the cell. The entrance of chloride-ions into the cell changes the charge across the neuronal membrane making it more difficult for the neuron to depolarize. It appears that the sedative-convulsant site is part of the chloride-ion channel.
GABA increases the size of the chloride-ion channel; the more GABA, the bigger the channel. Benzodiazepines increase the effect of small levels of GABA. Benzodiazepine blockers (flumazenil) do not inhibit the effect of GABA. GABA blockers, however, block the effect of Benzodiazepines. Alcohol, barbiturates and meprobamate, by stimulating the sedative convulsant site, enlarge the chloride-ion channel in the presence of basal levels of GABA. Picrotoxin and other convulsants prevent the widening of the chloride-ion channel even in the presence of large amounts of GABA. It has also been suggested that GABA may influence both dopamine and serotonin levels in the central and peripheral nervous systems.
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