SEDATIVE AND HYPNOTICS

Group 1

BARBITURATES

• Thiopental – Ultrashort-acting• Pentobarbital – Short-acting• Secobarbital – Short-acting• Amobarbital – Intermediate-acting• Barbital – Long-acting• Phenobarbital (Luminal®, Andral®) – Long-acting

History and Classification• From the beginning of the twentieth century, bromides

enjoyed a significant role in the U.S. as sedatives. With the advent of barbiturates in the 1940s, the use of bromides waned. Since then, barbiturates have been used traditionally for the alleviation of pain, anxiety, hypertension, epilepsy, and psychiatric disorders. Eventually, use of barbiturates would be replaced by other sedative-hypnotics (S/H) of comparable strength, namely chloral hydrate and meprobamate. Benzodiazepines would replace the traditional S/H as more effective, less toxic, and less addictive anxiolytics (sedatives).

• Today, the most popular therapeutic agents for anxiety (used for sedation), hypnosis (used for sleep), or anesthesia (for deep sleep) include buspirone (Buspar®) and zolpidem (Stilnox®).

• With the strict enforcement of controlled substances regulations, barbiturates have lost significant influence in both the therapeutic and illicit drug markets. Nevertheless, they are still the cause of 50,000 accidental and intentional poisonings per year, and their synergistic effects with ethanol are one of the leading causes of hospital admissions.

Medicinal Chemistry• Barbiturates are malonylurea derivatives (diureides),

synthesized from malonic acid and urea. The electron negative carbonyl carbons confer an acidic nature to the molecule, thus classifying them as weak acids. Allyl, alkyl, and allo-cyclic side chains determine their pharmacological classification.

Pharmacology and Clinical Use• Pharmacologically and clinically, barbiturates are

classified according to their duration of effect. The presence of longer and bulkier aliphatic and allocyclic side chains produces compounds that range from ultrashort-, short-, and intermediate to long-acting. Their major action is the production of sedation, hypnosis, or anesthesia through central nervous system (CNS) depression.

• The effect, however, depends largely on the dose, mental status of the patient or individual at the time of ingestion, duration of action of the drug, the physical environment while under the influence, and tolerance of the individual to this class of drugs. These factors determine the probability of a therapeutic or euphoric response.

Toxicokinetics and Metabolism• As a class, the barbiturates are largely nonionic, lipid-

soluble compounds, and their pKa ranges between 7.2 and 7.9.

• In general, an increase in the number of carbons and bulkier side chains results in enhanced lipid solubility, with a corresponding increase in toxicity. Attachment of a methylbutyl (1-mb) and replacement of the C2 with a sulfur group (as with thiopental) decreases its electron negativity, making it less acidic, more lipid soluble. Consequently, thiopental is an ultrashort-acting barbiturate used exclusively as a preoperative sedative/hypnotic.

• Rapid movement into and out of the CNS appears to determine rapid onset and short duration. Conversely, the barbiturates with the slowest onset and longest duration of action contain the most polar side chains (ethyl and phenyl with phenobarbital structure). Thus, phenobarbital enters and leaves the CNS very slowly as compared to the more lipophilic thiopental.

• In addition, the lipid barriers to drug metabolizing enzymes lead to a slower metabolism for the more polar barbiturates, considering that phenobarbital is metabolized to the extent of 10% per day.

• Similarly, distribution in biological compartments, especially the CNS, is governed by lipid solubility. Metabolism of oxybarbiturates occurs primarily in liver, whereas thiobarbiturates are also metabolized, to a limited extent, in kidney and brain. Phase I reactions introduce polar groups at the C5 position of oxybarbiturates, transforming the radicals to alcohols, ketones, and carboxylic acids. These inactive metabolites are eliminated in urine as glucuronide conjugates. Thiobarbiturates undergo desulfuration, to corresponding oxybarbiturates, and opening of the barbituric acid ring. Side chain oxidation at the C5 position is the most important biotransformation reaction leading to drug detoxification.

Mechanism of Toxicity• CNS depression accounts for all of the toxic manifestations

of barbiturate poisoning. The drugs bind to an allosteric site on the GABA-Cl ionophore complex (gamma-aminobutyric acid), an inhibitory neurotransmitter, in presynaptic or postsynaptic neuronal terminals in the CNS. This complex formation prolongs the opening of the chloride channel. Ultimately, by binding to GABAA receptors, barbiturates diminish the action of facilitated neurons and enhance the action of inhibitory neurons. Barbiturates concomitantly stimulate the release of GABA at sensitive synapses. Thus, the chemicals have GABA-like effects by decreasing the activity of facilitated neurons and enhancing inhibitory GABA-ergic neurons.

• Two major consequences account for the toxic manifestations:– 1.Barbiturates decrease postsynaptic depolarization by

acetylcholine, with ensuing postsynaptic block, resulting in smooth, skeletal, and cardiac muscle depression.

– 2.At higher doses, barbiturates depress medullary respiratory centers, resulting in inhibition of all three respiratory drives.

The neurogenic drive, important in maintaining respiratory rhythm during sleep, is initially inhibited. Interference with carotid and aortic chemoreceptors and pH homeostasis disrupts the chemical drive. Lastly, interruption of carotid and aortic baroreceptors results in a decreased hypoxic drive for respiration. Thus, with increasing depth of depression of the CNS, the dominant respiratory drive shifts to the chemical and hypoxic drives.

Signs and Symptoms of Acute Toxicity

• Clinical signs and symptoms are more reliable indicators of clinical toxicity than plasma concentrations.

• Signs and symptoms of barbiturate poisoning are related directly to CNS and cardiovascular depression. Reactions are dose-dependent and vary from mild sedation to complete paralysis.

• At the highest doses, blockade of sympathetic ganglia triggers hypotension, bradycardia, and decreased inotropy, with consequent decreased cardiac output.

• In addition, inhibition of medullary vasomotor centers induces arteriolar and venous dilation, further complicating the cerebral hypoxia and cardiac depression.

• Respiratory acidosis results from accumulation of carbon dioxide, shifting pH balance to the formation of carbonic acid. The condition resembles alcoholic inebriation as the patient presents with hypoxic shock, rapid but shallow pulse, cold and sweaty skin (hypothermia), and either slow, or rapid, shallow breathing.

• Responsiveness and depth of coma are evaluated according to the guidelines for the four stages of coma (Glasgow Coma Stage 1-4).

Clinical Management of Acute Overdose

• Treatment of overdose is symptomatic and follows the general guidelines adapted from the Scandinavian method for symptomatic treatment for CNS depressants.

• This includes maintaining adequate ventilation, keeping the patient warm, and supporting vital functions. To this end, oxygen support, forced diuresis, and administration of volume expanders have been shown to maintain blood pressure and adequate kidney perfusion and prevent circulatory collapse.

• If fewer than 24 hours have elapsed since ingestion, gastric lavage, induction of apomorphine emesis, delivery of a saline chathartic or administration of activated charcoal, enhances elimination and decreases absorption, respectively.

• In particular, multidose activated charcoal (MDAC) increases the clearance and decreases the half-life of Phenobarbital.

• Alkalinization of the urine to a pH of 7.5 to 8.0 increases clearance of long-acting barbiturates, while short- and intermediate-acting compounds are not affected by changes in urine pH.

• Should renal or cardiac failure, electrolyte abnormalities, or acid-base disturbances occur, hemodialysis is recommended.

• Although most cases of Phenobarbital overdose respond well to cardiopulmonary supportive care, severe cases will also require hemodialysis or charcoal hemoperfusion. Neither of these procedures will remove significant amounts of short- or intermediate-acting barbiturates. Through ion exchange, hemodialysis is more effective in removing long-acting barbiturates than short-acting compounds because there is less protein and lipid binding of the former.

• If renal and cardiac function are satisfactory, alkalinization of the urine and plasma with sodium bicarbonate promotes ionization of the acidic compounds. This maneuver hastens their excretion, provided that reabsorption and protein and lipid binding are minimized.

• Incorporation of CNS stimulants or vasopressors in the treatment protocol is not recommended, since mortality rates from pharmacological antagonism are as high as 40%.

• Even with complete recovery, complications affect prognosis. This includes the development of pulmonary edema and bronchopneumonia, infiltration with lung abscesses, and renal shutdown

Tolerance and Withdrawal• Pharmacodynamic tolerance (functional or adaptive)

contributes to the decreased effect of barbiturates, even after a single dose. With chronic administration of gradually increasing doses, pharmacodynamic tolerance continues to develop over a period of weeks to months, as the homeostatic feedback response to depression is activated in the presence of the compounds.

• Interestingly, no concomitant increase in LD50 is observed; rather, as tolerance increases, the therapeutic index decreases.

• Pharmacokinetic tolerance (drug dispositional) contributes less to the development of this phenomenon. Enhanced metabolic transformation and induction of hepatic microsomal enzymes ensues subsequent to pharmacodynamic tolerance, of which the former reaches a peak after a few days.

• In either situation, the effective dose of a barbiturate is increased six-fold, a rate which is primarily accounted for by the production of pharmacodynamic tolerance.

• Sudden withdrawal of barbiturates from addicted individuals runs the risk of development of hallucinations, sleeplessness, vertigo, and convulsions, depending upon the degree of dependency.

Methods of Detection• The immunoassays, enzyme-multiplied

immunoassay technique (EMIT) and radioimmunoassay (RIA), are designed to identify unmetabolized secobarbital in the urine. Both assays will detect other commonly encountered barbiturates as well, depending on the concentration of drug present in the sample.

• Positive tests for Phenobarbital have been noted in chronic users up to several weeks after discontinuation. Thin layer chromatography (TLC) is less sensitive than most chromatographic techniques but can demonstrate the presence of barbiturates up to 30 hours.

• Some reliable methods used for confirmation of the barbiturates include gas chromatography with flame ionization detection after derivatization (GC/FID), GC with nitrogen phosphorus detection (GC/NPD), and GC with mass spectroscopy (GC/MS).

• Confirmation of positive results from tests performed with immunoassay or TLC may be difficult. More specific GC and GC/MS procedures may not be able to confirm the metabolites screened with TLC.

Antidote

Prehospital Care

Ensuring adequate airway, breathing, and circulation is essential. Secure the airway and make sure the patient has good breath sounds bilaterally and is not hypotensive.

Perform an emergent endotracheal (ET) intubation if the patient has a significantly depressed level of consciousness and is not able to maintain the airway or has signs of increased intracranial pressure, ventilatory failure, or hypoxia.

Prehospital Care

Administer supplemental oxygen and obtain venous access.

In cases of hypotension, 2 large-bore intravenous lines are necessary for the administration of intravenous fluids and medications. Measure blood glucose level, and administer naloxone 2 mg IV to all patients with an altered mental status.

Emergency Department Care

Treatment of the patient with barbiturate toxicity is predominantly supportive. The mainstay of treatment underscores the importance of preventing hypoxemia and hypotension. Management strategies generally fall into 3 major areas: supportive care, decontamination, and enhancement of elimination.

Assess the airway and adequacy of respiration, and perform ET intubation if necessary. Check ET tube placement if the patient has been intubated. If the patient has not been intubated, provide supplemental oxygen and continue to monitor his or her airway status. Obtain intravenous access and an initial pulse oximeter reading, and place the patient on a cardiac monitor. Measure blood glucose, and administer naloxone 2 mg IV to all patients with altered mental status.

Emergency Department Care

Obtain a rectal temperature to check for hypothermia. If the patient is hypothermic, immediately initiate a careful rewarming (to avoid precipitating a fall in blood pressure).

Aggressively initiate fluid therapy if the patient has a low blood pressure or appears to be in hypovolemic shock. Initiate treatment with pressors (eg, norepinephrine, dopamine) if shock persists or worsens. In general, initiate pressors after aggressive and adequate fluid resuscitation has been attempted and the patient is determined to be euvolemic.

Emergency Department Care

GI decontamination

Since barbiturates are well adsorbed by activated charcoal, an initial dose of 1 g/kg should be administered. A cathartic is often administered to prevent constipation and to facilitate more rapid passage of the charcoal because barbiturates slow intestinal motility. Only perform GI decontamination after the airway is protected and hemodynamic stabilization has been addressed. Activated charcoal orally or by nasogastric tube is recommended for all patients with potential barbiturate toxicity.

Multiple doses of activated charcoal (MDAC) have been shown to enhance elimination of phenobarbital and to reduce the serum half-life. The recommended adult dose is 15-20 g given orally every 6 hours.

Emergency Department Care

Enhanced Elimination to decrease the duration of ventilatory support, mitigate hypotension, and decrease morbidity/mortality.

Enhanced urinary elimination has been well established as a treatment for phenobarbital and butalbital. Phenobarbital's low pKa (4.2), higher water solubility, and slow hepatic metabolism with a subsequently long half-life allow a larger proportion of drug to be renally excreted. Urinary alkalinization is not recommended for short-acting barbiturates.

Enhancement of urinary elimination may be accomplished with an initial sodium bicarbonate bolus of 1 mEq/kg followed by a constant infusion. This infusion may be made by adding 100-150 mEq of sodium bicarbonate to 850 mL of D5 and titrating to maintain a urine pH of greater than 7.5 with an arterial pH of less than 7.50. The goal should be a urine output of 150-250 mL/h.

Emergency Department Care

If the treatment of naloxone is unsuccessful, hemodialysis or hemoperfusion may be considered, which is another step in the right direction. This will allow to become drug free.

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Trivia # 1!

• no specific antidote for barbiturate toxicity, there have been numerous publications outlining the possible clinical use of intravenous lipid emulsion (ILE) as an antidote. The suggested mechanism of ILE in lipophilic drug toxidrome is the formation of a lipid sink that acts to sequester lipophilic toxins, thereby decreasing the targeted drug concentration and toxicity.

• However, although ILE continues to be a therapy of interest, its role at this time is limited. A recent review of approximately 42 case reports with ILE use showed a possible benefit. It has been used in circumstances in which negative hemodynamics remain unresponsive to conventional supportive therapy.

Trivia # 2!

• Marilyn Monroe died from an overdose of barbiturates, as did George Sanders…..

• 36 years old

• eight milligram percent of chloral

hydrate (sleeping pills) and 4.5 milligram

percent of Nembutal (aka Pentobarbital)

• cause of death as

"acute barbiturate poisoning", resulting

from a "probable suicide"

• George Sanders

• He had taken five bottles of the

barbiturate Nembutal

• 65 years old

• suicide notes – “Dear World, I am

leaving because I am bored. I feel I

have lived long enough. I am leaving

you with your worries in this sweet

cesspool. Good luck. ”(with his

signature under the writing)

Trivia # 3!

• Some sleeping tablets, such as

barbiturates suppress REM sleep,

which can be harmful over a long

period.

Trivia # 4!

• Michael

Rabin[Violinist] of US

became dependent on

barbiturates

• His death was partially

linked to drug abuse.

• 35 years old

Trivia # 5!

• Musician Jimi Hendrix died on September 18, 1970 of a Barbiturate overdose.

Trivia # 5!

• Dorothy Kilgallen

• an American journalist and

television game show panelist

• died from a lethal combination

of barbiturates and alcohol in

November of 1965.

Trivia # 6!

• How did barbituric acid, the first compound

in a class of drugs known as barbiturates,

get its name?

ANSWER:

• Johann Friedrich Wilhelm Adolph von

Baeyer invented a new compound

called malonylurea in 1894.

Afterwards, he dropped into a local

pub, whose patrons were celebrating

St. Barbara, patron saint of

artillerymen. Inspired by the festivities,

Baeyer renamed his compound

barbituric acid.

Trivia # 7!

Street Names

• Nembies• Seggies• Chewies• Barbies• Barbs• Sleepers• Blue Bullets• Blue Devils• Gorillas• pink ladies

Trivia # 8!

• The first Barbiturates were made in the 1860s by the Bayer laboratories in Germany . In 1903, the first Barbiturate ("Barbital") was used in medical practices. In 1912, a common Barbiturate, Phenobarbital, was introduced.

Trivia # 9!

• The Barbiturate called Sodium Pentothal is known as "truth serum." However, it really does not cause people to tell the truth. Rather, it may lower a person's inhibitions and make people more talkative.

Trivia # 10!

• Barbiturates in high doses are used for physician-assisted suicide (PAS) and in combination with a muscle relaxant for euthanasia and for capital punishment by lethal injection.

Trivia # 11!

• Barbiturates have been used extensively in the past as sedatives. A new group of drugs called "Benzodiazepines" has replaced many of the Barbiturates. However, Barbiturates are still used to treat some types of Epilepsy.