PHARMACOLOGY CNS 2 ANXIOLYTICS, HYPNOTICS AND SEDATIVES SAMUEL AGUAZIM( MD)

Tolerance and Dependence Tolerance is a physiology state characterized by a reduced drug effect with repeated use of the drug. Higher doses are needed to produce the same effect. Cross-tolerance means that individuals tolerant to one drug will be tolerant to other drugs in the same class, but not to drugs in other classes

Tolerance and Dependence Dependence is characterized by signs and symptoms of withdrawal when drug levels fall. Cross-dependence means that individuals dependent to one drug will be dependent to other drugs in the same class, but not to drugs in other classes Note: Cross-tolerance and Cross-dependence occur between all of the CNS sedatives, including the barbiturates, benzodiazepines and ethanol.

ANXIOLYTICS, HYPNOTICS AND SEDATIVES Define anxiety: an unpleasant emotional state consisting of apprehension, tension and feelings of danger, without a real or logical cause. Physical symptoms include: tachycardia, tachypnea, sweating, trembling and weakness

ANXIOLYTICS, HYPNOTICS AND SEDATIVES A sedative drug decreases activity, moderates excitement, and calms the recipient. B. A hypnotic drug produces drowsiness and facilitates the onset and maintenance of a state of sleep that resembles natural sleep, and from which the patient can be easily aroused. C. An anxiolytic drug reduces anxiety.

Organization of Class 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. They depress behavior, moderate excitement, induce calmness, and may produce drowsiness or even loss of consciousness. The sedative-hypnotics are used clinically as anti-anxiety agents, muscle relaxants, sleep inducers, anti-epileptics, and as preanesthetic medications.

Major classes of drugs used to treat anxiety? Benzodiazepines- the most frequently used drugs for anxiety Azaspirones- for example, buspirone Carbamates- for example, meprobamate Barbiturates- rarely used today because of severe side effects and a low therapeutic index. These drugs have generally been replaced by the benzodiazepines.

BENZODIAZEPINES SHORT –ACTING (2-8 HOURS) OXAZEPAM( serax) Clonazepam(klonopin) Midazolam (versed) Triazolam (halcion) INTERMEDIATE ACTING ( 10-20 HOURS) Temazepam (restoril) Lorazepam ( ativan) Alprazolam ( xanax)

BENZODIAZEPINES LONG- ACTING ( 1-3 DAYS) Chlordiazepoxide ( librium) Diazepam ( valium) Flurazepam ( dalmane) NEUROTRANSMITTER INVOLVED GABA( y-aminobutyric acid) is the major inhibitory neurotransmitter of the CNS.

Mechanism of action Barbiturates and benzodiazepines act similarly to produce depression of central nervous system function and behavior. Barbiturates enhance the function of y-aminobutyric (GABA)in the CNS. Benzodiazepines bind to a specific site associated with GABAд receptor which results in increased inhibition.

WHAT ARE THE THERAPEUTIC INDICATIONS FOR BENZODIAZEPINES These drugs are used clinically as muscle relaxants and in the treatment of the following: Anxiety disorders Panic disorders- alprazolam is the drug of choice Status epilepticus- diazepam is the drug of choice Sleep disorders Insomnia- all benzodiazepines can be sedating but lorazepam and temazepam are the most commonly used. Alcohol withdrawal- Chlordiazepoxide most commonly used.

BENZODIAZEPINES What is their route of administration? PO, IV or IM Where are benzodiazepines metabolized? They are metabolized in the liver and excreted in urine. Does dependence occur? Yes. Prolonged use can result in dependence. Abrupt discontinuation can result in withdrawal symptoms, including confusion, anxiety and agitation.

What type of symptoms may a patient taking benzodiazepines experience? Drowsiness and confusion- the most common side effects Ataxia Dizziness Respiratory depression and death, if taken with other CNS depressants such as ethanol.

Anxiolytic and Sedative-Hypnotics STAGES OF CNS DEPRESSION. With increasing dosage:  Calming or drowsiness {sedation} Sleep {pharmacological hypnosis} Unconsciousness Surgical anesthesia Coma Fatal respiratory/cardiovascular depression

Benzodiazepines antagonist: Flumazenil ( romazicon) MECHANISM OF ACTION OF FLUMAZENIL It is a competitive antagonist of benzodiazepines at the GABA A RECEPTOR. Clinical use: reversal of benzodiazepine sedation or overdose How long do the effects of Flumazenil last? Only 1 hour- repeat doses may be necessary for a heavily sedated patient to remain alert.

AZASPIRONES: BUSPIRONE ( BuSpar) MECHANISM OF ACTION: It acts as a partial agonist of serotonin ( 5HT1A ) receptor. Clinical use of this drug. Buspirone is used for generalized anxiety; however, unlike benzodiazepines, its effects may take 2 weeks to become apparent. This drug metabolized by the liver and excreted in the urine. Buspirone differs from benzodiapines because it lacks muscle relaxant and anticonvulsant properties of the benzodiazepines

What advantages does buspirone have over benzodiazepines? Minimal sedation Low abuse potential No overdose fatalities reported No withdrawal symptoms What toxic effects are associated with buspirone? Headache Nausea Dizziness

CARBAMATES: MEPROBAMATE What is meprobamate’s mechanism of action? It is not well known. Clinical use: It is now virtually obsolete. In the past it was used primarily in the treatment of anxiety. What are the adverse effects? Respiratory depression-major toxic effect Hypotension Shock Heart failure

BARBITURATES EXAMPLES OF BARBITURATES PHENOBARBITAL (LUMINAL)- LONG ACTING PENTOBARBITAL (NEMBUTAL )- SHORT ACTING AMOBARBITAL ( AMYTAL)- SHORT ACTING THIOPENTAL ( PENTOTHAL)- ULTRASHORT-ACTING

WHAT ARE THE THERAPEUTIC INDICATIONS FOR BARBITURATE ADMINISTRATION Induction of anesthesia- thiopental Anticonvulsants- e.g, phenobarbital Treatment of anxiety Induction of hypnosis Why are benzodiazepines favored over barbiturates for the treatment of anxiety? Benzodiazepines have a much higher therapeutic index than do barbiturates

BARBITURATES By what routes can barbiturates can be administered? IV, PO OR IM What are the pharmacokinetic properties of barbiturates? they are metabolized in the liver and all induce cytochrome P-450 and excreted in the urine Redistribution to other tissues determines the duration of action of thiopental.

BARBITURATES Does barbiturate dependency occur? Yes- abrupt cessation can lead to severe withdrawal symptoms ( tremor, restlessness, nausea, seizures and cardiac arrest) Contraindication: not given to patients who have acute intermittent porphyria, because they increase porphyrin synthesis

BARBITURATES What are the adverse effects of these drugs? Drowsiness and decreased motor control Induction of the P-450 system Addiction Respiratory depression and coma in high doses Allergic reactions, especially in patients with asthma

OTHER SEDATIVES( benzodiazepine receptor agonist Zalephon, Zolpidem and eszopiclone are known as non-benzodiazepine receptors agonist ( NBBRAS) ZOLPIDEM (AMBEIN) Describe this drugs clinical use Treatment of insomnia (SHORT TERM) What are its adverse effects? Ataxia and Confusion

CHLORAL HYDRATE CLINICAL USES: HYPNOSIS SEDATION ( in children) Describe this drug’s adverse effects. Gastrointestinal distress Unpleasant taste

Melatonin Receptor Agonist Ramelteon is a selective agonist at the MT₁ and MT₂ subtypes of melatonin receptors. This drugs help one fall asleep 7-16 minutes faster. Side effect: dizziness, fatigue and somnolence