Pharm 100 - Lesson B.3
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History of Use - sedatives and hypnotics
- The first agents to be introduced into clinical medicine as sedatives and hypnotics were the bromides in the mid 19th century. Prior to that, ethyl alcohol and herbal preparations were the only drugs available. Unfortunately, bromides are eliminated at a slow rate from the body and the drug accumulated. This produced a condition known as bromism, characterized by mental and neurological aberrations, skin rash and gastrointestinal disturbances.
- Chloral hydrate and paraldehyde were introduced shortly after bromide and were found to be safer drugs.
- In 1912, the introduction of phenobarbital heralded the age of the barbiturates.
- In the 1950's, meprobamate and glutethimide were introduced and enjoyed considerable success.
- In 1961, chlordiazepoxide was introduced and ushered in the era of the benzodiazepines. These drugs are widely used today and indeed much overused
Therapeutic Uses of sedatives and hypnotics
- (a) Antianxiety relief: The benzodiazepines are the drugs of choice.
- (b) Sedative (reduce sensory-motor function, reduce tension): The wide margin of safety of the benzodiazepines allows these drugs to be used in clinical situations where sedation is required.
- (c) Hypnotic (sleep): The short-acting benzodiazepines are the drugs most widely used as hypnotics.
- (d) Anticonvulsant agent for certain types of epilepsy: Phenobarbital has been used to control generalized tonic-clonic and partial seizures. Some of the benzodiazepines are useful in absence seizures and status epilepticus.
- (e) Treatment of skeletal muscle spasm: Benzodiazepines reduce elevated skeletal muscle tone and are useful in neuromuscular disorders, e.g. cerebral palsy.
- (f) Treatment of alcohol withdrawal syndrome: Most of the benzodiazepines are useful in the treatment of alcohol withdrawal. Diazepam is the drug of choice.
Benzodiazepines - Mechanism of CNS Action
- In 1977, specific receptors for the benzodiazepines were discovered in the nervous system. These receptors are highest in density in the cerebral cortex, cerebellum and limbic system. These drugs:
- (a) Increase synaptic inhibition and thus dampen neuronal responses.
- (b) By activating the benzodiazepine receptor, they enhance the action of gamma-aminobutyric acid(GABA), the major inhibitory neurotransmitter in the CNS. The sites of action include the cerebellum, cerebral cortex, limbic system, reticular activating system, and the spinal cord.
Pharmacological Properties of Benzodiazepines (8)
- They possess a very high therapeutic index
- They produce relief from anxiety
- They can decrease aggression.
- They produce sedation and amnesia
- Some members of this group are effective hypnotics (drowsiness, facilitates onset and maintenance of sleep).
- They produce minimal suppression of rapid-eye-movement (REM)-type sleep with hypnoticbenzodiazepines (e.g. flurazepam) at normal doses.
- They produce skeletal muscle relaxation (e.g. diazepam)
- They have anticonvulsant action (e.g. diazepam for status epilepticus), i.e. an acute episode of seizures
Pharmacokinetics: - Benzodiazepines
This is the pharmacological property for which there are appreciable differences among the various benzodiazepines. They have different durations of action, which is determined by rate of liver metabolism and formation or lack of pharmacologically active metabolites. The individual benzodiazepines have similar pharmacological profiles, but are used for different purposes. Diazepam isused as an anxiolytic and anticonvulsant. Flurazepam is used as a hypnotic. Alprazolam is the drug ofchoice for panic disorders.
Routes of administration - Benzodiazapines
Benzodiazepines are usually taken as a capsule or tablet, but some areavailable for intravenous use.
Effects of short-term use – low to moderate doses Benzodiazepines
- CNS; the desirable effects are the relief from anxiety and tension, relaxation and calmness. Other effects may include mild to moderate impairment ofmotor coordination, drowsiness, lethargy, fatigue, and impairment of thinking and memory
- Respiratory depression has been observed following rapid intravenous administration.
- Gastrointestinal symptomsare nausea, constipation, dry mouth and abdominal discomfort. Moderate doses of all benzodiazepines can impair motor coordination and impair driving. There is conflicting evidence as to the extent of the effect moderate doses of benzodiazepines have on automobile accidents, but as the effect on any oneindividual is not known, it is suggested that patients taking these drugs during the day refrain from driving or operating dangerous machinery.
Effects of short-term use – higher doses - Benzodiazepines
The major effect of higher doses are drowsiness, oversedation and sleep. Prior to sleep, the clinical picture may resemble an intoxicated state. The subjectwould have blurred vision, incoordination, slow reflexes, and impaired thought. These symptomsbecome more intense as the dose is increased. At very high doses, sleep may proceed to coma. Comacan result from lower doses if the benzodiazepines are taken with other CNS depressants (e.g. alcohol).
Effects of long-term use: - Benzodiazepines
The effects of long-term use varies between individuals. Someindividuals can take large amounts for long periods of time without any major evidence of intoxication,while others will demonstrate the symptoms of chronic sedative-hypnotic intoxication. These are: impaired thinking, poor memory and judgement, disorientation, slurred speech, incoordination, and weakmuscles.
Lethality: - Benzodiazepines
The benzodiazepines are among the drugs most commonly involved in overdose. Fortunately, the wide margin of safety for these drugs means that deaths from overdoses are very rare. Death has occurred following ingestion of enormous doses, rapid intravenous injection of a large dose, orwhen a large dose was taken in combination with other drugs
Tolerance - Benzodiazepines
Tolerance develops to the sedative and impairment of coordination effects of the benzodiazepines. Tolerance to the anxiolytic effect is less common. Tolerance does not appear to be a problem for theclinical use of these drugs, but tolerance may develop to the desired effects (euphoria) when the drugs areused for non-therapeutic purposes. A high degree of cross tolerance occurs among the benzodiazepinesand other sedative-hypnotic drugs such as barbiturates and alcohol.
Physical dependence/withdrawal: - Benzodiazepines
It is generally acknowledged that, for the millions of patientswho take benzodiazepines for short periods (up to a few months), the risk of physical dependence is low. If use is chronic (one year or more), sudden discontinuation of the drug may lead to withdrawal symptoms. The severity of the withdrawal is determined by the individual benzodiazepine used, the dose and duration of use, as well as the abruptness of stopping the drug. The symptoms would include agitation, paranoia, seizures and delirium. These extreme symptoms occur much less frequently thanwith the barbiturates. There has been a lot of debate whether or not withdrawal symptoms occur afterstopping therapeutic doses of the benzodiazepines. There is evidence that a mild but distinct withdrawaloccurs, exhibiting anxiety, headache, insomnia, tension, difficulty concentrating, and fatigue.
Psychological dependence - Benzodiazepines
Psychological dependence (addiction) may develop in some users, but by no means all. There is apersistent craving for the drug, even when it no longer produces an effect.
Patterns of use: - Benzodiazepines
The benzodiazepines are among the most widely prescribed drugs in the world. Ten percent of Canadians use a benzodiazepine at least once a year for medical reasons. Abuse anddependence on the benzodiazepines for recreational purposes does occur. Diazepam and lorazepam arethe preferred drugs and are often used in combination with alcohol to enhance the effect of alcohol. Interestingly, 30-76% of alcohol abusers use benzodiazepines.
Potential for abuse: - Benzodiazepines
Benzodiazepines have a low abuse liability. They have weaker reinforcingproperties than barbiturates, alcohol, opioids and stimulants. The inherent harmfulness is also low. The margin of safety is high; they may make one uncoordinated, but they do not depress respiration atthese doses and do not often lead to death.
- The barbiturates are potent CNS depressants. At low doses, they induce a state of relaxation andtranquillity and will mildly impair cognitive (thinking) and motor function.
- At moderate doses, they caninduce sleep, but prior to inducing sleep, they can impair motor and cognitive functions. This moderatelyimpaired state can be pleasurable.
- At higher doses still, they induce anesthesia, i.e. a state of unconsciousness where powerful or painful stimuli are not experienced. As the dose increases, theycause greater and greater depression of the respiratory centre in the brain. Death results from respiratoryfailure.
- The clinical uses for the barbiturates is limited. The short-acting ones are used to induce anesthesia,and phenobarbital (a long-acting agent) is used as an antiepileptic. They have been replaced for the mostpart by newer and safer drugs.
- Common street names are barbs, downers and goofballs. Other street names are based on the colour of the capsule, e.g. red devils for Seconal
Mechanism of Action - barbiturates
The action of the barbiturates is less selective than that of the benzodiazepines on the CNS. Barbiturates interfere with the transport of ions across the neuronal cell membrane. The ion transport isnecessary for transmission of neural signals. In addition, they potentiate the effect of GABA at itsreceptor, enhancing the inhibitory effect of GABA, but they do not bind to the benzodiazepine receptor.
Pharmacological Properties - barbiturates
- 1. They possess a low therapeutic index. The dose required to produce a beneficial effect is close tothe dose that will produce a toxicity.
- 2. The barbiturates demonstrate a full spectrum of dose-dependent CNS depression.Antianxiety ÷ sedation ÷ hypnosis ÷ general anesthesia ÷ death.
- 3. When used as a hypnotic (e.g. secobarbital), they suppress REM-type sleep. REM sleep is essentialso that we do not wake up feeling "not having slept".
- 4. Some of the long-acting barbiturates are effective in suppressing epileptic seizures.
- 5. Thiopental, an ultrashort-acting drug, is used to induce general anesthesia. It also suppressesrespiration, but the patient is artificially ventilated.
- 6. Respiratory depression is a major problem and is dose-dependent.
- 7. The cardiovascular system is depressed by high doses. The response usually seen is a slowing of theheart and lowering of blood pressure.
Barbiturates are classified according to
- Barbiturates are classified according to their duration of action:
- Long-acting (1-2 days), e.g. phenobarbital.
- Short-acting (3-8 hours), e.g. secobarbital (seconal).
- Ultrashort-acting (20 minutes), e.g. thiopental.
Routes of administration: - barbiturates
For medical use in epilepsy, the usual route is oral. To induce anesthesia, the route is intravenous. The recreational use of barbiturates is usually oral. Some users (e.g.heroin addicts) will inject barbiturates in order to obtain the "rush effect", despite the inherent dangers.
Effects of short-term use – low doses - barbiturates
Low doses usually result in tranquillity, relaxation, mildeuphoria, and reduced interest in one's surroundings. There may also be dizziness and mild impairmentof motor coordination. Movements or activities requiring fine motor dexterity are especially affected.
Effects of short-term use – moderate doses: - barbiturates
Moderate doses induce sleep. Prior to sleep, there is aperiod of increased activity (the drug inhibits an inhibitory pathway), a pleasurable state of intoxication,and euphoria. Some individuals will become hostile and aggressive. Other effects are similar to thosewith lower doses, but of greater magnitude. There may be a small decrease in blood pressure andrespiration.
Effect of short-term use – high doses - barbiturates
Sleep is highly probable and the subject may loseconsciousness. All other responses are as described above, but become progressively greater in magnitude as the dose is increased. At very high doses, death results from respiratory depression.
Effects of long-term use: - barbiturates
Chronic inebriation is the term which best describes long-term use. Memory, judgement and thinking are impaired. The person exhibits hostility and mood swings,including depression.
Lethality - barbiturates
Lethality with barbiturates is common, especially when combined with alcohol. There are nospecific antidotes for barbiturate poisoning as there is with the opioids. A number of deaths also resultduring barbiturate withdrawal.
Tolerance - barbiturates
Tolerance can develop very rapidly to sleep induction and the mood effects of the barbiturates, oftenwithin a few weeks of nightly administration. Tolerance develops more slowly to the impaired motorcoordination and slowed reaction time. Tolerance to the anticonvulsant actions develops much moreslowly and does not appear to be a major problem clinically. There is a high degree of cross tolerance between barbiturates, and between barbiturates and other sedative-hypnotics.
Psychological dependence - barbiturates
Psychological dependence (addiction) on barbiturates can result from regular use, irrespective of thedose. Users crave the psychological effects of the drug, even though they may not use it every day. There may be a feeling of panic if they cannot get an adequate supply. The craving often persists longafter use has stopped.
Physical dependence/withdrawal - barbiturates
Physical dependence/withdrawal usually follows abrupt discontinuance of the barbiturates. Thesyndrome following withdrawal after low doses presents as sleep disturbances. A more severewithdrawal syndrome occurs if cessation follows chronic use. Symptoms occur in 12 to 24 hours andinitially appear as tremors, anxiety, weakness and insomnia, as well as rapid drop in blood pressure whenthe person goes from sitting to standing. There is also severe weakness, a hyperactive blink and other reflexes. The symptoms peak between 24 and 72 hours after the last administration and may eventuallyinclude seizures, delirium, visual hallucinations, and a high body temperature. The person may notsurvive the seizures and fever. If the person survives, the symptoms will decline after several days. Thebarbiturates must be withdrawn slowly under medical supervision to prevent the withdrawal syndrome.
Patterns of use: - barbiturates
Barbiturates are prescribed much less in 2010 than 40 years ago. Illicit usecontinues to be a problem. Barbiturates are sometimes combined with heroin and the mixture givenintravenously to obtain a pleasurable "high". Similarly, barbiturates are combined with methamphetamine and the claim is that the euphoria with the combination is greater than either drugalone.
Potential for abuse: - barbiturates
- The abuse liability of the barbiturates is equal to or greater than alcohol Thepleasurable effects of some of the barbiturates give a significant degree of reinforcement.
- The inherentharmfulness of the barbiturates is very high. The risk of death from respiratory depression or fromwithdrawal is high. These drugs should be avoided.
Flumazenil is a GABAA receptor antagonist and blocks the effect of the benzodiazepines. It can beused as an antidote for benzodiazepine poisoning.
Zolpidem is a new GABA receptor agonist and may have advantages over the benzodiazepines as ahypnotic as it does not disturb sleep patterns to the same extent as the benzodiazepines.
Buspirone does not act on the GABA receptor, but rather at the 5-HT receptor. It is used ingeneralized anxiety states and may have an advantage over other sedatives in that it does not appear tohave an additive effect with other sedative-hypnotic drugs.
Chloral hydrate is an old drug that was once widely used as a hypnotic. It is used occasionally inthe geriatric patient. It causes epigastric distress (heartburn) and an unusual taste in the mouth. There islimited rationale for its use.
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