Anti-Anxiety Agents and Sedative-Hypnotics CNS DEPRESSANTS Anti-Anxiety Agents and Sedative-Hypnotics

INTRODUCTION Anxiety is an unpleasant state of tension, apprehension or uneasiness from an unknown source. Symptoms are similar to those of fear and is due to sympathetic activation Symptoms of Chronic, severe, debilitating anxiety requires treatment Hypnosis simply means sleep inducing All antianxiety drugs cause sedation, and can also function as anxiolytic and hypnotic agents.

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.

CLASSIFICATION Barbiturates Benzodiazepines Are the two major categories of sedative-hypnotics Other anxiolytic drugs Nonbarbiturate sedatives

BENZODIAZEPINES (BDZs) Are the most widely used anxiolytic drugs Have replaced barbiturates in the treatment of anxiety cos are more effective and safer.

Mech of action GABA-A receptors is the target for BDZs. It binds to a site on GABA-A called BDZ receptors Binding of GABA to its receptor opens the chloride channel causing hyperpolarization. MOA: binding of BDZs to a site on GABA-A receptor potentiates the effect of GABA by ↑ing the frequency of opening of chloride channel.

Benzodiazepines DIAZEPAM ALPRAZOLAM LORAZEPAM CLONAZEPAM FLURAZEPAM TEMAZEPAM QUAZEPAM MIDAZOLAM ESTAZOLAM TRIAZOLAM

ACTIONS Reduction of anxiety: at low doses and acts via enhancing the effects of GABA by binding to GABA-A receptors. Sedative and hypnotic: at higher doses via binding to GABA-A and enhancing the effect of GABA Anterograde amnesia: causes temporary impairment of memory by binding to GABA-A receptors. Anticonvulsant: used to treat epilepsy

Muscle relaxant: at high doses All BDZs have neither anesthetic nor analgesic property

Therapeutic uses Anxiety disorders: that accompanies depression and schizophrenia. Panic disorder, phobias: alprazolam Muscular disorder: diazepam Amnesia Seizures: clonazepam, diazepam(grand mal and status epilepticus) Clorazepate, chlordiazepoxide, diazepam, oxazepam and lorazepam useful for treatment of alcohol withdrawal

continuation Sleep disorders: Flurazepam: ↑es duration of sleep, ↓es number of awakenings and its long acting Temazepam: used in pts who experience freq wakening Triazolam: used to induce sleep in pts with insomnia.

PHARMACOKINETICS BDZs are rapidly and completely absorbed after oral administration. Duration of action: Long acting BDZs (1-3days):clorazepate, chlordiazepoxide, diazepam, flurazepam and quazepam Intermediate acting(10-20 hours): alprazolam, estazolam, lorazepam, temazepam Short-acting (3-8 hours): oxazepam, triazolam

Fate of BDZs Most are metabolized by the hepatic P450 system to compunds that are also active. Their effects are terminated by excretion or redistribution. All BDZs cross the placenta

PRECAUTIONS LIVER FAILURE (most BDZs). Some are not metabolized by the liver and so can be given to pts with liver disease. It includes Oxazepam, Temazepam, Lorazepam. These drugs are not metabolized in liver. ( remember the first letters OTL – Outside The Liver) Alcohol and other CNS depressants enhance the sedative-hypnotic effects of BDZs Should be avoided in pts with narrow angle glaucoma

ADVERSE EFFECTS DROWSINESS, CONFUSION ATAXIA Cognitive impairment DEPENDENCE : PSYCHOLOGICAL, PHYSICAL WITHDRAWAL : ANXIETY, TENSION,CONFUSION, restlessness, REBOUND INSOMNIA (Triazolam)

Benzodiazepine antagonist FLUMAZENIL GABA receptor antagonist Rapidly Reverses the effect of benzodiazepines. I.V. route only. Used for treatment of BDZs poisoning SE: Nausea, vomiting, agitation and dizziness.

OTHER ANXIOLYTIC DRUGS BUSPIRONE HYDROXYZINE ZOLPIDEM ZALEPLON

OTHER ANXIOLYTICS - BUSPIRONE Site of action: binds to 5-HT1A receptor subtype. No anticonvulsant activity. No interaction with benzodiazepine binding sites No muscle relaxant properties and causes minimal sedation Minimal adverse effects USED FOR GAD Generalized Anxiety Disorders Slow onset of action  

ZOLPIDEM ACTS ON BENZODIAZEPINE RECEPTORS though not a BDZ. HYPNOTIC NO ANTI CONVULSANT NO MUSCLE RELAXTION MINIMAL REBOUND INSOMNIA ONSET OF ACTION – FAST METABOLIZED BY P450 TO INACTIVE COMPOUND HALF LIFE – SHORT ( 3 HOURS) SE: NIGHTMARES, GI UPSET, DAYTIME DROWSINESS

ZALEPLON Similar to zolpidem in its hypnotic actions but causes fewer side effects compared to zolpidem or BDZs. Has a half life of < 1hour Metabolized by cyt P450 system.

Barbiturates Were formerly the mainstay of treatment used to sedate the patient or to induce and maintain sleep. Have been replaced by BDZs cos they induce tolerance, physical dependence, severe withdrawal symptoms and coma in toxic doses.

DRUGS PHENOBARBITAL – LONG ACTING PENTOBARBITAL SECOBARBITAL Both are short acting THIOPENTAL – ULTRA SHORT ACTING ( 20 MIN)

BARBITURATES MECH OF ACTION : Bind to GABA-A receptors potentiating the effect of GABA by prolonging the duration of chloride channel opening.

Actions Anesthesia Treatment of seizures Sedative(low dose) and hypnotic agents(high doses) Depression of CNS and can lead to coma and death. Respiratory depression Induces P450 in the liver No analgesic action

Therapeutic uses Anesthesia: thiopental an ultra-short acting barbiturate is used intravenously to induce anesthesia. Anticonvulsant: phenobarbital used in the long term management of tonic-clonic seizures, status epilepticus Anxiety: used as sedatives to relieve anxiety, nervous tension, insomnia at low doses

pharmacokinetics Readily cross the placenta and can depress the fetus. Are metabolized by the liver except phenobarbital Excreted in urine Barbiturate + alcohol = bad combination

ADVERSE EFFECTS Drowsiness CNS: Impaired concentration, sluggishness HANG OVER: Hynoptic doses METABOLISED IN LIVER CI : ACUTE INTERMITTENT PORPHYRIA DEPENDENCE: WITHDRAWAL SEVERE: MAY CAUSE DEATH

Barbiturate poisoning Severe depression of respiration CVS depression Shock Treatment: artificial respiration,gastic lavage, hemodialysis, alkalinzation of urine. No specific barbiturate antagonist available

NONBARBITURATE SEDATIVES Chloral hydrate Antihistamine ethanol

OTHER SEDATIVES ANTIHISTAMINES : diphenhydramine, doxylamine are effective in treating mild types of insomnia CHLORAL HYDRATE SEDATIVE AND HYPNOTIC SE: GI UPSET TASTE CHANGES PREFERRED ROUTE : PER RECTAL

ETHANOL Is a CNS depressant at high doses Anxiolytic Produces sedation Hypnosis with increasing dosage. Crosses the placenta Metabolized in the liver first to acetaldehyde by alcohol dehydrogenase and then to acetate by acetaldehyde dehydrogenase

ALCOHOL METAB

CNS CHR. EFFECT DEPRESSION, MEMORY LOSS RISK FOR SEIZURES WERNICKES – KORSAKOFFS ENCEPHALOPATHY Metabolic effects: hypoglycemia, gout, lactic acidosis

CVS : ACUTE : VASODILATION HIGH DOSES : VASOCONSTRICTION IN HEART CHRONIC: MYOCARDIAL DEPRESSION GIT : ACUTE : STIMULATES ACID HIGH : DIRECT IRRITATION CHRONIC: DIARRHOEA / CONSTIPATION,, PANCREATITIS

RESPIRATORY DEPRESSION LIVER : CHR : CIRRHOSIS RESPIRATORY DEPRESSION CHRONIC :IMPOTENCE, TESTICULAR ATROPHY, GYNAECOMASTIA PREGNANCY : FETAL ALCOHOL SYN. LOW IQ, MICROCEPHALY, FACIAL ABNORMAILITIES.

continuation Elimination: kidney(MC), lung Alcohol withdrawal is treated with BDZs

Disulfiram Blocks the oxidation of acetaldehyde to acetate by inhibiting acetaldehyde dehydrogenase Results in the accum of acetaldehyde in the blood causing unpleasant symptoms such as flushing, tachycardia, hyperventilation, nausea Used in pts seriously desiring to stop alcohol ingestion.

OTHER ALCOHOLS METHANOL : FORMS FORMIC ACID EFFECTS : BLINDNESS, SEVERE ACIDOSIS.. Respiratory failure… Ethylene glycol: forms OXALIC ACID Side effect: acute tubular necrosis, CNS depression, acidosis

Treatment for overdose Fomepizole: long acting inhibitor of alcohol dehydrogenase IV Ethanol: for methanol and ethylene glycol poisoning