ANXIOLYTICS-SEDATIVES-HYPNOTICS

BYDR. P. EMEKA

COCP-KFU

LECTURE OBJECTIVES

• 1. Define and differentiate anxiolytics, Sedative-hypnotic drugs.

• 2. Classify them.• 3. Determine their MOA and relate their

pharmacokinetics to adverse reactions associated with their use.

Overview• Variety of drugs have the capacity to depress the

function of the CNS such that • calming or drowsiness (sedation) is produced.

Older sedative-hypnotic drugs depress the CNS in a dose-dependent fashion: progressively producing calming sedation sleep unconsciousness surgical anaesthesia coma and ultimately, fatal depression of respiration and cardiovascular regulation.

General Definitions1. Anxiolytic: Reduce anxiety

physical, emotional, cognitive

2. Sedative: Calm down and relieve agitation.

3. Hypnotic: Induce sleepgo to sleep fast, feel refreshed tomorrow !!!

An effective anxiolytic should reduce anxiety and exert a calming effect with little or no effect on motor or mental functions (i.e

sedation).

Sedatives- reduce nervousness, excitability, and irritability without sleep

A hypnotic drug should produce drowsiness and encourage the onset and maintenance of a state of sleep that as far as possible resembles the natural sleep state.

Sedative-hypnotics are drugs which depress or slow down the body's functions.

Often these drugs are referred to as tranquilizers and sleeping pills or sometimes just as sedatives.

Their effects range from calming down anxious people to promoting sleep. Both tranquilizers and sleeping pills can have either effect, depending on how much is taken.

At high doses or when they are abused, many of these drugs can even cause unconsciousness and death.

Barbiturates Benzodiazepines 

Non-Benzodiazepines

drugs

Miscellaneous agents 

1. Amobarbital 2. Pentobarbital 3. Thiopental 4. Secobarbital 5.Phenobarbital

1. Diazepam 2. Midazolam 3. Clonazepam 4. Chlordiazepoxide 5. Flurazepam 6. Triazolam 7. Lorazepam 8. Flumazenil* *receptor antagonist

Second generation agents1. Zolpidem 2. Zaleplon3. Zopiclone

1.Chloral hydrate 2. Paraldehyde 2. Meprobamate 3. Buspirone

CLASSIFICATION

NeurophysiologyGABA controls the excitability of neurons by binding to the GABA A receptor. The GABA A receptor is a protein complex located in the synapses of neurons. All GABA A receptors contain an ion channel that conducts chloride ions across neuronal cell membranes and two binding sites for the neurotransmitter GABA.Chloride ions entering the cell stabilize the membrane and make it more difficult for excitatory transmitters to fire the cell.

All sedatives-hypnotics are positive GABAA modulators – They increase the ability of GABA to open the chloride (Cl-) ion channel.

At low doses, both Barbiturates and Benzodiazepines enhance the effect of GABA, but at high doses, barbiturates can open the ion channel.

BarbituratesFirst introduced in 1903, standard agents for insomnia and sedation.• Habit-forming• Barbiturates have a very narrow therapeutic

index.Notorious enzyme inducers

• Barbiturates also have weak analgesic effects.• They produce a wide spectrum of effects, from

mild sedation to anaesthesia. 

BARBITURATES: Classification(1). Ultra-short-acting barbiturates: act within seconds, and their duration of action is 30min. Mephobexital, thiamylal, thiopental. Thiopental is used as an anesthesia.

(2). Short-acting barbiturates: have a duration of action of about 2h. The principal use : sleep-inducing hypnotics.

Pentobarbital, secobarbital.

(3) Intermediate-acting barbiturates: have and effect lasting 3-5h. Butabarbital, Amobarbital. The principal use of

Amobarbital is as hypnotics.

(4) Long-acting barbiturates: have a duration of action greater than 6h. Such as Barbital and Phenobarbital. Therapeutic

uses: hypnotics and sedative, and antiepileptic agents at low doses.

MECHANISM OF ACTION1. Barbiturates enhance the action of GABA.

2. They bind to a different site on the GABA-receptor/chloride channel, and prolong the duration of the opening of GABA-activated chloride channels.3. Barbiturates also block the effects glutamate, the excitatory neurotransmitter.

Barbiturates depress the CNS at all level in a dose-dependent fashion.

Now it is mainly used in anaesthesia and treatment of epilepsy; use as sedative-hypnotic agents is no longer recommended.

Pharmacokinetics1. Its high lipid solubility allows rapid transport across the

blood-brain barrier and results in a short onset.

2. Barbiturates are distributed widely, and they readily cross the placenta.

3. They are metabolised in the liver where they activate activities of glucuronyl transferase and CYPs 1A2, 2C9, 2C19, and 3A4.

Barbiturates and their metabolites are excreted e urine.

Alkalinization of the urine expedites the excretion of barbiturates.

Treatment of acute over dosage: Sodium bicarbonate.

Therapeutic uses of barbiturates

1. Sedative-hypnotic agents

2. Used in the emergency treatment of convulsions as in status epilepticus.

3. Anaesthetic (or be given before anesthetic)

4. Combination with antipyretic-analgesic

5. Treatment of hyperbilirubinemia and kernicterus in the neonate.

Adverse effects of Barbiturates

After effect: hangover---dizzy, drowsiness, amnesia, impaired judgment, disorientation.

Tolerance: decreased responsiveness to a drug following repeated exposure because of down-regulation of receptors and induction of hepatic drug-metabolizing enzymes.

Adverse effects Contd.• Dependence: including psychologic and physiologic

dependence.

• Withdrawal symptoms: excitation, insomnia, tremor, anxiety, hallucinations and sometimes convulsions.

• Depressant effect on respiration: (Potentially Fatal Respiratory Depression due to narrow therapeutic range), can cross the placental barrier during pregnancy and secrete into breast milk.

• Others: Skin eruptions and porphyria.

• Sedative -------------------------> hypnotic• Effects resemble alcohol – drugs of abuse!!

Treatment of acute over dosageAn overdose can result in coma, diminished reflexes, severe respiratory depression, hypotension leading to cardiovascular collapse, and renal failure.

Treatment (A.B.C): (1) supporting respiration and circulation. (2) alkalinizing the urine and promoting diuresis. (3) Hemodialysis or peritoneal dialysis.

Effects of combining sedative-hypnotics with alcohol

• Taken together, alcohol and sedative-hypnotics can kill.

• The use of barbiturates and other sedative-hypnotics with other drugs that slow down the body, such as alcohol, multiplies their effects and greatly increases the risk of death.

• Overdose deaths can occur when barbiturates and alcohol are used together, either deliberately or accidentally.

Benzodiazepines

Benzodiazepines are a class of mild tranquilizers

that prevent or reduce anxiety symptoms by affecting the inhibitory neurotransmitter

 gamma-aminobutyric acid (GABA). 

Could be classified as either: Anxiolytic, or

Sedative-hypnotic depending on the dose.

They have abuse for potential.

Classified into short-acting and long-acting.

Benzodiazepines

They are the most frequently prescribed sedative-hypnotics.

• Most commonly prescribed drug classes.• Favorable side effects.• Efficacy.• Safety.

MECHANISM OF ACTION

Benzodiazepines affect GABA neurotransmitter in the brain.

Benzodiazepines enhance the activity of GABA, effectively slowing nerve impulses throughout the body. The human nervous system has two different types of benzodiazepine receptors: one that causes the anti-anxiety effect, and one that elicits the sedative effect.

Effects on the CNS1. With increasing doses, benzodiazepines can progressive cause sedation, then hypnosis and then stupor.

2. Can not produce general anaesthesia since awareness persists.

3. Have anti-anxiety / sedative-hypnotic properties.

4. Few have effective muscle relaxants, whereas most others are not. 

PHARMACOKINETIC OF BENZODIAZEPINES

1. Well absorbed when given orally.2. They bind strongly to plasma protein.3. High lipid solubility cause many of them to accumulate gradually in body fat. 4. Persist longer in obese, elderly.5. Fast across blood-brain-barrier: rapid onset of action. 6. Distribution volumes is big.7. Transformed in the liver by microsomal drug-metabolizing enzyme systems.

Therapeutic Uses1. Major indication is for anxiety (because of

their anxiolytic properties). 2. Effective as sedative/hypnotics:-

Therefore useful in treatment ofa. Insomniab. Effective muscle relaxantsc. Generate anterograde amnesia

3. Panic attacks and phobias4. Treatment of alcohol withdrawal5. Effective anticonvulsant•      

Side EffectsMost Common: Mental confusion, disorientation, Drowsiness, lethargy.

Less common: Muscular incoordination, ataxia, short term anterograde amnesia, slurred speech, dementia and Seizures may occur if drug is discontinued abruptly.

Tolerance may develop and rebound insomnia has been reported.

Abuse Potential of BenzodiazepinesThere is a low incidence of abuse and dependence if taken for a short time. However, prolonged use can lead to dependence and result in withdrawal

Withdrawal symptoms include:

a. Return of anxiety state,

b. increases in rebound insomnia,

c. restlessness,

d. agitation,

e. irritability

Advantages of BENZODIAZEPINES over BARBITURATES

They have high therapeutic index.

Ingestion of even 20 hypnotic doses does not usually endanger life (Safety).

Hypnotic does not affect respiration or cardiovascular functions.

Higher doses produce mild respiration & hypotension which is problematic only in patients with respiratory insufficiency (COPD) & cardiac abnormality. BZDs have practically no action on other body system .

Effects on pregnancy They can freely cross the placental barrier and accumulate in fetal circulation.

Usage during the first trimester can result in foetal abnormalities.

Also usage in third trimester can result in foetal dependence, or “floppy-infant syndrome”

Benzodiazepines are also excreted in the breast milk

Effects in Overdose• Unconsciousness• Respiratory depression• Collapse of heart and heart functions• Walking difficulty• CNS depression• Shallow breathing

– Not being able to take full, deep, normal breaths.

Flumazenil is used as an effective antagonist of benzodiazepines

FlumazenilFlumazenil is a benzodiazepine antagonist, which also binds the same receptors as benzodiazepines.

1. Has high affinity for benzodiazepine receptor

2. It behaves as a Competitive antagonist.

3. It is used as antidote to benzodiazepine overdose.

4. The sedative effects of benzodiazepines are antagonized.

5. Onset of action is fast when given parentally for symptomatic treatment, producing immediate effects.

6. Has a very short half life.

Adverse effects

7. Agitation

8. Confusion

9. Dizziness

10. Precipitation of abstinence syndrome in patients with benzodiazepine dependence

11. Nausea with repeated dose.

Non- barbiturate sedative-hypnoticsChloral hydrate (1) relatively safe hypnotic, inducing sleep in

a half hour and lasting about 6h. (2) used mainly in children and the elder,

and the patients when failed to other drug.MOA:- general CNS depressant, can exert barbiturate-like effects on GABAA-receptor channels

IND: Insomnia

Pk: prodrug:- converted to trichloroethanol

ParaldehydeParaldehyde is a hypnotic and sedative with antiepileptic effects. It is occasionally used to control status epilepticus resistant to conventional treatment.Onset: Hypnosis: Oral: Within 10-15 min; IM: Within 2-3 min.Duration: 6-8 hrAbsorption: Readily absorbed; slower after rectal than after oral or IM doses. It has a strong odour and a disagreeable taste.Distribution: Widely distributed; Half-life: 4-10 hr. Crosses the placenta, distributed into breast milk.Metabolism: Hepatic (approx 70-80% of a dose), to acetaldehyde, which is oxidised by aldehyde dehydrogenase to acetic acid.Excretion: Approx 30% as unchanged drug in expired air via the lungs; trace amounts via urine unchanged.

Meprobamate

• Has muscle relaxant activity and blocks inter-nuncial neurons in spinal cord.

• It is not used now because of abuse liability and hypnotic actions, safer drugs are available

BuspironeUsed in chronic anxiety (elderly) or mixed anxiety-depression states.No GABA effects, less sedation, euphoria, psychomotor impairment.Absence of abuse potential, wide margin of therapeutic safetySigns of over dose: drowsiness and euphoria.Supportive treatment

Second generation agents1. Zolpidem Acts like a benzodiazepine

MOA:-Binds to (subtype 1) GABAA1 receptors. Primarily a sedative w/o anxiolytic Useful for the short-term treatment of insomnia, anticonvulsant, or muscle-relaxant effects.  Memory is affected• Adverse Effects Drowsiness, dizziness, and nausea at therapeutic doses.Flumazenil reported to reverse memory impairments and overdoses

Other 2nd generation agents (Nonbenzodiazepine)

Zaleplon & Zopiclone

They are agonist that acts at the GABAA1 receptors like

benzodiazepines.

They have short half-life

Only approx. 30% of an orally administered dose reaches the plasma, and most of that undergoes first-pass elimination.

Less potent than zolpidem

  Improves sleep quality w/o rebound insomnia, and little chance of developing dependency

Side Effects

Nausea VomitingAnterograde amnesia HallucinationsDelusions Altered thought patterns

• amnesia is a loss of the ability to create new memories after the event