Sedatives, Hypnotics, and Alcohol Notes

Key Terms

• Automatism: Drug-induced confusion that can cause increased drug consumption.
• Barbiturate: CNS depressant drug possessing the barbituric acid ring structure.
• Benzodiazepine: Class of drugs used to treat anxiety and sleep disorders.
• GABA: Gamma-aminobutyric acid, an inhibitory neurotransmitter in the CNS.
• Hypnotic: Drug used to induce and maintain sleep.
• Nonbarbiturate: Sedative-hypnotic drugs that do not possess the barbituric acid structure, such as benzodiazepines and related drugs.
• NREM sleep: Stages of sleep characterized by nonrapid eye movement (NREM).
• REM sleep: Stages of sleep characterized by rapid eye movement (REM) and dreaming.
• Sedative: Drug used to produce mental relaxation and to reduce the desire for physical activity.

Learning Outcomes

• LO 12.1: Describe the stages of the sleep cycle and the main characteristics of each stage.
• LO 12.2: Explain the mechanism of action of the sedative-hypnotic drugs in relationship to their actions with GABA and the chloride ion channel.
• LO 12.3: Describe the adverse effects of barbiturates, the addiction liability, and treatment of barbiturate overdose.
• LO 12.4: Explain the mechanism of action of the benzodiazepine hypnotics and the pharmacokinetic differences between the short-acting and longer-acting drugs.
• LO 12.5: Explain the mechanism of action of eszopiclone, zaleplon, and zolpidem and the advantages of these drugs over barbiturates and benzodiazepines.
• LO 12.6: Describe the major pharmacologic effects and adverse reactions of ethyl alcohol.

Introduction to Sedatives and Hypnotics

• The central nervous system (CNS) coordinates and controls the activities of all other body systems.
• CNS stimulation results in alertness, anxiety, and irritability; excessive stimulation can cause convulsions or abnormal behavior (e.g., amphetamine or cocaine abuse).
• CNS depression reduces physical and mental activity; excessive depression leads to unconsciousness, coma, and death (e.g., narcotics, barbiturates, and alcohol abuse).
• Sedatives and hypnotics decrease CNS activity and are essentially the same drugs, but sedatives are given at lower dosages.
  • Sedatives reduce the desire for physical activity, often prescribed after a heart attack to prevent overexertion.
  • Hypnotics induce and maintain sleep (treat insomnia), which is crucial as excessive tiredness can worsen anxiety.
• The Emotional Reaction to the Gradual Depression of the Central Nervous System: Stressors (marriage, unemployment, exams, old age, bills, work) can lead to a tense state, which can be managed with tranquilizing (calming), sedative, or hypnotic drugs to induce a drowsy or asleep state.
• Hypnotics should be used intermittently and only when needed, typically limited to 2-4 weeks due to tolerance development and decreased effectiveness with prolonged use.
• Sedatives and hypnotics include barbiturates and nonbarbiturates.
  • Barbiturates are rarely used due to high abuse potential and addiction liability.
  • Nonbarbiturates include benzodiazepines and miscellaneous drugs.

Sleep Cycle

• Sedative-hypnotic drugs can alter the normal sleep cycle.
• The sleep cycle is divided into two states: nonrapid eye movement (NREM) and rapid eye movement (REM) sleep.

NREM Sleep

• Divided into four stages; progression from stage 1 to 4 takes 60-90 minutes, characterized by a deeper level of sleep.
• Stage 1:
  • Individuals are relaxed but still somewhat aware of their surroundings; eyes are usually closed.
  • Alpha waves predominate.
  • Lasts a few minutes and occupies 4-5% of total sleep time.
• Stage 2:
  • Individuals become unaware of surroundings but can be easily awakened.
  • Brain waves are increased in amplitude compared to alpha waves but occur at a lower frequency.
  • Occupies about 50% of total sleep time.
• Stages 3 and 4:
  • Referred to as "slow-wave sleep" due to high-amplitude, low-frequency delta waves observed on the EEG.
  • Deeper stages of sleep are important for physical rest and restoration.
  • Occupy approximately 20-25% of total sleep time.
  • The amount of time spent in slow-wave sleep decreases with aging which contributes to insomnia.

REM Sleep

• Characterized by bursts of rapid eye movement, increased autonomic activity, and dreaming.
• Essential for mental restoration; daily events are reviewed, and information is integrated into memory.
• EEG records beta-type waves (similar to the waking state).
• Individuals are harder to awaken from REM sleep than other sleep stages (referred to as “paradoxical sleep”).
• Occupies about 20-25% of total sleep time.
• Most individuals go through four to six sleep cycles per night, depending on the length of sleep.
• Brain waves from an electroencephalogram (EEG) are useful in evaluating sleep disorders.

Mechanism of Action of Sedative-Hypnotic Drugs

• Brain activity depends on neurotransmitters (either stimulate or inhibit neuronal activity).
• Gamma-aminobutyric acid (GABA) is an essential inhibitory neurotransmitter which consists of approximately 50% of the inhibitory activity of the brain and spinal cord.
• Neuronal function also depends on ions like sodium ($Na^+$), potassium ($K^+$), and chloride ($Cl^-$).
  • Ions move in (influx) or out (efflux) of the neuronal membrane through specific ion channels.
  • Nerve action potentials are generated when $Na^+$ ions influx through sodium channels to depolarize (make the inside more positive) the nerve membrane.
  • Nerve action potentials are inhibited when $Cl^-$ ions influx through chloride channels to hyperpolarize (make the inside more negative) the nerve membrane.
  • GABA regulates the chloride channel.

GABA and the Chloride Channel

• The chloride channel is composed of five subunits: two alpha, two beta, and one gamma, forming a circular channel that allows $Cl^-$ ions to pass through the nerve membrane into the neuron.
• GABA binds to a specific site on the channel referred to as the GABA receptor.
• GABA binds to the GABA receptor, the channel opens, and $Cl^-$ ions influx into the nerve, causing hyperpolarization, which reduces the generation of action potentials and inhibits neuronal activity.
• The chloride channel also contains receptor sites for barbiturates, benzodiazepines, and other hypnotic drugs, which increases GABA receptor-mediated chloride influx by binding to specific drug receptor sites on the chloride channel.
  • Barbiturates prolong the duration of channel opening, which increases $Cl^-$ ion influx and have additional inhibitory actions both related and unrelated to the chloride channel.
  • Benzodiazepines bind to their receptors, named the benzodiazepine receptors (BZD receptors), increasing the activity of GABA by increasing the frequency of chloride channel opening.
  • Drugs such as zaleplon, zolpidem, and eszopiclone demonstrate a more selective binding to a subunit of the benzodiazepine receptor ($BZD_1$ receptor), which offers certain hypnotic advantages over barbiturate and benzodiazepine drugs.
• Each of these drug classes acts to facilitate the inhibitory actions of GABA to increase chloride ion influx.

Barbiturate Sedatives and Hypnotics

• Barbiturates are among the oldest drugs in the sedative-hypnotic class.
• Their use as hypnotics has been mostly replaced by newer drugs due to numerous disadvantages.
• All barbiturates are structurally similar to barbituric acid and produce a dose-dependent depression of the CNS; and can produce general anesthesia at higher doses.
• They are still available and indicated for conditions other than hypnosis.

Mechanism of Action

• At lower doses, barbiturates bind to drug receptors on the GABA receptor-mediated chloride ion channel, which increases the influx of chloride ions, which results in hyperpolarization of nerve membranes, which decreases the activity of the reticular activating system (RAS), promoting sedation or sleep, depending on the dosage.
• At higher doses, barbiturates cause a general depression of the entire CNS, similar to general anesthetics, which is related to their ability to dissolve in neuronal membranes, interfering with the normal function and movement of ions that regulate neuronal excitability and the release of excitatory neurotransmitters.

Effect of Barbiturates on the Sleep Cycle

• When used as hypnotics, barbiturates usually increase stage 2 sleep but decrease slow-wave sleep (stages 3 and 4), also suppresses REM sleep.
• Discontinuation often leads to spending excess time in REM sleep during the next night or two to make up for the lost REM sleep (REM rebound), which causes increased dreaming that may cause restlessness, anxiety, and nightmares.
• Disruption of the normal sleep cycle is another reason barbiturates are no longer recommended as hypnotics.

Pharmacokinetics

• Barbiturates are well absorbed following oral administration and readily distributed to all tissues; symptoms of CNS depression occur within 30-60 minutes following oral administration.
• The drug microsomal metabolizing system (DMMS) in the liver is responsible for inactivation.
• Taken regularly for more than several days, barbiturates begin to induce the microsomal enzymes, resulting in faster metabolism of the barbiturate.
• With prolonged administration, the duration of action is decreased, and patients must take larger doses of the drug to attain the same pharmacologic effect as before (drug tolerance).
• When enzyme induction of the metabolizing enzymes occurs, all of the drug-metabolizing enzymes are increased; other drugs metabolized by the microsomal enzymes are also metabolized faster, responsible for a number of drug interactions.
• Barbiturates are eliminated mostly by the urinary system.

Barbiturate Drugs

• Phenobarbital (Luminal):
  • Classified as a long-acting barbiturate, with a duration of 6-12 hours.
  • When used as a hypnotic, may produce a “hangover effect.”
  • Also used as an anticonvulsant drug in the treatment of epilepsy.
• Pentobarbital (Nembutal):
  • Classified as an intermediate-acting sedative-hypnotic, with a duration of 4-6 hours.
• Amobarbital (Amytal):
  • Similar to pentobarbital.
  • Both pentobarbital and amobarbital can be used parenterally to stop convulsions.
• Secobarbital (Seconal):
  • A short-acting hypnotic, with a duration of 2-4 hours.
  • The hypnotic indication is for individuals who have difficulty falling asleep but not staying asleep.

Adverse Effects

• Adverse effects are an extension of their therapeutic action (CNS depression), including drowsiness, dry mouth, lethargy, and incoordination.
• Depressed reflexes and impaired judgment may contribute to serious accidents if patients operate motor vehicles or heavy machinery while taking these drugs.
• Elderly patients are particularly sensitive to CNS side effects, especially mental confusion and memory difficulties.
• Impaired memory due to CNS depression may cause patients to retake the drug repeatedly and experience an overdose (automatism), leading to drug intoxication and death.
• Mild overdosage resembles alcohol intoxication (inebriation), including slurred speech, ataxia, impaired judgment, irritability, and psychologic disturbances.

Addiction Liability

• Prolonged and excessive use results in tolerance and physical dependence.
• Cross-tolerance (resistance) develops to the depressant effects of other CNS depressants, such as alcohol and benzodiazepines, because the mechanism of action of all these drugs involves the interaction with GABA and the chloride ion channel.
• The mechanism for the production of tolerance and dependency has not yet been clearly determined.
• Physical dependency usually develops when greater therapeutic dosages are taken on a regular basis for more than 1-2 months.
• Once physical dependence develops, the drug must be used continuously to avoid the onset of withdrawal symptoms, including anxiety, insomnia, cramping, tremors, paranoid behavior, delirium, and convulsions.
• The abstinence syndrome (withdrawal) is especially dangerous; convulsive seizures and death may occur if withdrawal is not conducted within an adequately supervised medical center.

Barbiturate Poisoning

• Overdose results in extensive cardiovascular and CNS depression.
• In large doses, these drugs depress all brain activity, including that of the vital centers in the medulla oblongata.
• Inhibition of vasomotor centers in the medulla oblongata removes sympathetic control of the blood vessels, contributing to hypotension and shock.
• Hypotension decreases kidney function, leading to little or no urine production (oliguria or anuria) to remove the toxic products from the body.
• Medullary respiratory centers are also depressed, leading to irregular breathing and hypoxia (cyanosis).
• Severe intoxication usually leads to coma, respiratory depression, and death.
• There is no antidote; treatment includes supportive therapy to maintain respiration and blood pressure.
• Endotracheal intubation and artificial respiration may be employed; sympathomimetic (alpha-adrenergic) drugs and intravenous (IV) fluids may be administered to elevate blood pressure.
• Osmotic diuretics administered intravenously may stimulate urine production so that renal excretion of the drug can occur.
• Alkalinization of the urine (pH 7.0 or above) will increase the excretion of the more acidic barbiturates, like phenobarbital.
• Hemodialysis or peritoneal dialysis may be required when kidney function is depressed.

Cautions and Contraindications

• Barbiturates are the drugs frequently used for attempted suicide; short-acting drugs are particularly dangerous due to their rapid action.
• To prevent hospitalized patients from hoarding medication, always make sure they have swallowed the sedative-hypnotic at the scheduled time.
• Barbiturates are contraindicated in patients who have acute intermittent porphyria because sedative-hypnotics stimulate and increase the production of porphyrins, which can precipitate an attack (nerve damage, pain, paralysis) in patients prone to this condition.

Pregnancy

• Barbiturates are designated as Food and Drug Administration (FDA) Pregnancy Category D, indicating they can cause harmful effects to the fetus; should be avoided during pregnancy.

Drug Interactions

• Sedative-hypnotic agents will potentiate the actions of other CNS depressant drugs, leading to greater CNS and respiratory depression; should never be taken together with alcohol.
• Barbiturates cause enzyme induction, other drugs may be metabolized more rapidly, resulting in a decreased pharmacologic effect of drugs such as oral anticoagulants and oral contraceptives.
• Most sedative-hypnotic drugs are bound to plasma proteins; therefore, they compete with other drugs for protein-binding sites; protein-binding displacement usually leads to a potentiation of the pharmacologic effect of the drug displaced.

Benzodiazepines

• Benzodiazepines are a class of drugs widely used in the treatment of anxiety (antianxiety drugs).
• In addition to producing antianxiety effects, all benzodiazepines exert sedative, hypnotic, muscle relaxant, and anticonvulsant effects, which are useful in a variety of clinical conditions.
• Several benzodiazepines are marketed specifically as hypnotics.
• The benzodiazepines are also the drugs preferred for producing sedation; diazepam, alprazolam, and lorazepam-are more frequently used to treat anxiety.

Mechanism of Action

• Benzodiazepines produce sedative and hypnotic effects by increasing the inhibitory activity of gamma-aminobutyric acid.
• Benzodiazepines bind to their drug receptor sites (BZD receptors) that are in close relationship to the GABA receptors.
• The combined action of GABA and the benzodiazepine drug increases the frequency of chloride ion channel opening, resulting in hyperpolarization of the nerve membrane and reduced neuronal activity.
• In the reticular activating system, this depression produces sedation or hypnosis, depending upon the dose of drug administered.

Pharmacokinetics

• Benzodiazepines are lipid-soluble drugs that readily enter the CNS and are well absorbed after oral administration.
• They are metabolized by the drug microsomal enzymes.
• Some are metabolized to active metabolites, which also produce sedation and hypnosis and prolong the duration of action.
• Unlike barbiturates, benzodiazepines do not cause enzyme induction of the microsomal metabolizing enzymes at therapeutic doses, and are eliminated mainly by way of the urinary tract.

Drug Examples

• Flurazepam (Dalmane):
  • Classified as a long-acting benzodiazepine.
  • It forms several active metabolites, some of which have long half-lives.
  • Sedative and antianxiety effects are usually evident the day following a hypnotic dose.
  • Prolonged action can be useful in anxious patients when sedating drug effects are desired during the following day; daytime sedation and drowsiness may interfere with employment or other activities.
• Temazepam (Restoril):
  • Intermediate-acting hypnotic that does not form any essential active metabolites.
  • The duration of hypnotic action is 8-10 hours, and there are usually little or no drug effects evident the following day.
  • One preparation is marketed in a hard gelatin capsule that gives a delayed onset of action and should be taken 1-2 hours before sleep is desired.
• Triazolam (Halcion):
  • Short-acting hypnotic with no active metabolites.
  • This hypnotic does not usually cause residual effects the day following a hypnotic dose.
  • The short duration of action may cause early-morning awakenings.

Effects on Sleep Cycle

• NREM stage 2 is increased, while NREM stage 4 is usually decreased.
• Do not significantly suppress REM sleep and, therefore, do not usually cause REM rebound when discontinued.

Advantages of Benzodiazepine Hypnotics over Barbiturates

• Generally do not interfere with REM sleep.
• Produce less tolerance and, therefore, are effective for a few weeks longer than barbiturates when taken on a nightly basis.
• Also do not induce microsomal metabolizing enzymes significantly.
• When abused, benzodiazepines generally cause less physical dependence than barbiturates.
• These factors, along with a lower incidence of adverse effects, give the benzodiazepines a number of advantages over the barbiturates for both sedation and hypnosis.

Adverse Effects

• Benzodiazepine hypnotics are well tolerated and produce few adverse effects when used properly.
• Flurazepam, because of its longer half-life, may cause sedation or a “hangover effect" the following day.
• Triazolam, which has a very short duration of action, has been associated with rebound insomnia.
• Triazolam has been associated with increased daytime anxiety.

Use of Flumazenil (Romazicon)

• Flumazenil is a benzodiazepine receptor antagonist that may be administered intravenously to reverse the depressant effects of the benzodiazepine drugs.
• It can be used in the management of benzodiazepine overdose to antagonize the effects of excessive CNS and respiratory depression.
• Flumazenil has a half-life of approximately 1 hour and may require repeated administration; the sedative effects of eszopiclone, zaleplon, and zolpidem also are antagonized by flumazenil.

Cautions and Contraindications

• Benzodiazepine hypnotic drugs have been shown to cause harmful effects during pregnancy; they are designated as FDA Pregnancy Categories D and X and, therefore, should not be used during pregnancy.

Drug Interactions

• Benzodiazepines potentiate the actions of other CNS depressant drugs, such as alcohol and barbiturates; such drugs should never be taken together unless specifically ordered by a physician.
• The metabolism of the benzodiazepines has been shown to be inhibited by cimetidine (Tagamet), a drug used in the treatment of intestinal ulcers; cimetidine and other drugs that cause enzyme inhibition can increase the duration of action of the benzodiazepines.

Miscellaneous Hypnotic Drugs

• The miscellaneous drugs are a diverse group of drugs with differing chemical structures and pharmacologic characteristics, including eszopiclone, zaleplon, and zolpidem.
• These hypnotics bind selectively to a subunit of the benzodiazepine receptor to increase the inhibitory effects of GABA.
• These drugs lack other pharmacologic actions such as anticonvulsant, muscle relaxing, and antianxiety effects produced by benzodiazepines and barbiturates and do not disrupt the normal stages of sleep like barbiturates and benzodiazepines.
• These drugs appear to be at low risk for the development of drug tolerance, dependency, and withdrawal reactions; other miscellaneous drugs include ramelteon and chloral hydrate.

Drug Examples

• Eszopiclone (Lunesta):
  • Rapidly absorbed after oral administration, with a half-life of approximately 6 hours.
  • Studies have demonstrated that eszopiclone sustained its ability to induce and maintain sleep when taken daily for 6 months; there is little evidence for the development of drug tolerance or dependency; abrupt cessation of drug following prolonged use may result in some withdrawal reactions.
  • Common adverse effects include dizziness, headache, dry mouth, and mild impairment of memory.
• Zaleplon (Sonata):
  • Rapidly absorbed and provides a short duration of action; it is useful for individuals having difficulty falling asleep; it has not been shown to increase total sleep time.
  • Adverse effects include dizziness, headache, and minor GI disturbances; the elderly may experience mental confusion and memory disturbances; tolerance and dependency do not appear to be a significant problem, and any withdrawal reactions are usually associated with abrupt cessation of the drug following prolonged use.
• Zolpidem (Ambien, Ambien-CR):
  • Currently the most widely prescribed hypnotic drug on the market; rapidly absorbed and has a quick onset of action.
  • Zolpidem decreases awakenings during the night and increases total sleep time.
  • The extended-release tablets supplied by Ambien-CR (controlled release) further prolong the duration of action; newer immediate-release formulations include Zolpimist (5 mg per actuation) and sublingual tablets (Edluar 5 mg and 10 mg, and Intermezzo 1.75 mg and 3.5 mg).
  • As with eszopiclone and zaleplon, drug tolerance, dependency, and withdrawal reactions are usually associated with abrupt cessation of drug following prolonged use; common adverse effects include headache, dizziness, and nausea; the elderly may experience some confusion and memory disturbances.
• Ramelteon (Rozerem):
  • Classified as a melatonin agonist; melatonin is produced by the pineal gland, released mainly at night, and involved with the regulation of the sleep-wake cycle.
  • The main effect of the drug is to promote sleep onset and should be taken 30 minutes before bedtime; adverse effects include headache, dizziness, and minor GI disturbances such as nausea and diarrhea; is not a controlled substance and is not associated with drug dependency.
• Chloral Hydrate:
  • An old drug and is related in a general way to alcohol; in the liver, it is metabolized by alcohol dehydrogenase to trichloroethanol, which also produces hypnotic effects (active metabolite).
  • Main use is as a hypnotic, particularly in the elderly; the usual dosage is 500 to 1000 mg administered as capsules or syrup; rectal suppositories are also available.
  • Produces less suppression of REM sleep than do the barbiturates; side effects usually involve excessive CNS depression and gastric irritation; although capable of producing tolerance and addiction, chloral hydrate is not particularly popular with drug abusers.

Preferred Therapy for Insomnia and Sedation

• The preferred hypnotics for individuals having problems falling asleep and staying asleep are usually miscellaneous drugs such as zolpidem (Ambien, Ambien-CR) or eszopiclone (Lunesta), which cause minimal drug tolerance and dependency. When taken nightly, they are effective for longer periods than barbiturates or benzodiazepines.
• For individuals with insomnia complicated by anxiety or stressful situations, benzodiazepines like temazepam (Restoril) or estazolam (ProSom) provide an intermediate duration of action with little or no residual effects the following day.
• Flurazepam (Dalmane) or quazepam (Doral) may be considered when residual sedative and antianxiety actions are desired the following day.
• For individuals whose main problem is falling asleep, shorter-acting drugs like zaleplon (Sonata) or the OTC drug ramelteon (Rozerem) may be helpful.
• The preferred drugs for sedation are usually one of the benzodiazepine drugs (diazepam (Valium), alprazolam (Xanax), and lorazepam (Ativan).
  • The sedative dosage varies depending on the desired degree of sedation but generally is one-third to one-half of the hypnotic dose.

Patient Administration and Monitoring

• Monitor vital signs and patient response when barbiturates and benzodiazepines are administered parenterally.
• Explain the potential drug side effects: excessive drowsiness, mental confusion, and a drug hangover effect the following day.
• Explain to patients the dangers of activities such as driving while under the influence of sedative and hypnotic drugs, and the dangers of combining alcohol and other CNS depressant drugs with sedatives and hypnotics.
• Remind patients that these drugs should not be used for more than 2 weeks, and warn patients of the potential for drug dependency when barbiturate and benzodiazepine hypnotics are used continuously for prolonged periods.

Alcohol

• Alcohol (ethanol, whiskey, ethyl alcohol, or grain alcohol) is probably the most widely used (self-prescribed) nonprescription sedative-hypnotic and antianxiety agent.

Pharmacologic Effects

• Alcohol has many pharmacologic effects that are seen throughout the body, including the CNS, heart, gastrointestinal tract, and kidneys.

CNS Effects

• The CNS is extremely sensitive to the depressant action of alcohol.
• Alcohol produces a dose-dependent depression of the CNS.
• After drinking alcoholic beverages, people usually feel “stimulated,” uninhibited, and less self-conscious, but this stimulation is actually due to an initial depression of inhibitory areas within the brain.
• As the level of alcohol in the brain increases, excitatory and inhibitory fibers are progressively depressed, leading to sedation, hypnosis, and possibly coma.
• Unlike the other sedative-hypnotic drugs, alcohol produces some analgesia and antipyresis (reduces fever).
• The mechanisms of alcohol's action in the CNS have not been fully established, but alcohol also appears to increase the inhibitory effects of GABA.

Vascular Effects

• In low to moderate amounts, alcohol does not produce any direct deleterious effects on the heart.
• Alcohol may induce dilation of the blood vessels in the skin (cutaneous), producing a warm, flushed sensation.
• The dilation of blood vessels may lead to a rapid loss of body heat, so that body temperature begins to fall.
• Depression of vasomotor centers in the CNS is most likely responsible for producing the peripheral vasodilation.

Gastrointestinal Effects

• Alcohol stimulates the secretion of saliva and gastric juices (acid and pepsin),resulting in an increased appetite.
• Ingestion of strong concentrations of alcohol may irritate the gastric mucosa, causing a local inflammation (gastritis).
• Increased acid secretion coupled with gastritis may lead to GI ulceration in sensitive patients.

Renal Effects

• Alcohol promotes an increased excretion of urine (diuresis), which is partly due to the increased fluid intake that accompanies the ingestion of alcoholic beverages.
• Alcohol blocks the pituitary secretion of antidiuretic hormone (ADH), which decreases the renal reabsorption of water to be excreted into the urine.
• Alcohol inhibits the renal secretion of uric acid, allowing uric acid to build up in the blood. In susceptible patients (with gout or gouty arthritis), this elevation in uric acid levels may lead to attacks of joint inflammation.

Nutritional Effects

• Alcohol exerts a profound influence on the nutritional state of individuals.
• Alcohol is a natural product that possesses calories; many people often substitute alcohol for nutritionally rich foods, such as protein.
• Over a period of time, individuals who consume moderate to large amounts of alcohol in conjunction with a poorly balanced diet may suffer from vitamin and amino acid deficiencies.
• B vitamin deficiency leads to abnormal growth and function of nervous tissue, producing conditions such as neuropathies, dermatitis (pellagra), anemia, and psychosis.

Metabolism of Alcohol

• Alcohol is readily absorbed throughout the entire GI tract following ingestion and is distributed to all tissues.
• The CNS receives a significant concentration of alcohol because of its rich blood supply; alcohol concentration in the brain is proportional to alcohol concentration in the blood.
• Unlike other drugs, alcohol is metabolized at a constant rate in the liver; only 10 to 15 ml of pure alcohol per hour is metabolized (amount of alcohol in one beer, a glass of wine, or an average-size cocktail).
• Alcohol is metabolized primarily to acetaldehyde, which the body can use in the synthesis of cholesterol and fatty acids; alcohol is efficiently metabolized (about 95%) to useful biochemical products and water.
• Enzyme induction develops during chronic use of alcohol; habitual drinkers experience shorter durations of action of other drugs metabolized by the microsomal system of the liver (oral anticoagulants).

Adverse Effects

• The adverse effects associated with the use of alcohol are classified into acute and chronic effects.
• Acute intoxication (inebriation) produces extensive CNS depression; individuals may exhibit ataxia, impaired speech, blurred vision, and loss of memory, similar to the symptoms of intoxication caused by other sedative-hypnotic drugs.