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

2. 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.

3. 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.

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

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

7. 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.

9. Benzodiazepines DIAZEPAM ALPRAZOLAM LORAZEPAM CLONAZEPAM FLURAZEPAM
TEMAZEPAM
QUAZEPAM
MIDAZOLAM
ESTAZOLAM
TRIAZOLAM

10. 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

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

12. 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

13. 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.

14. 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

15. 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

16. 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

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

18. 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.

19. OTHER ANXIOLYTIC DRUGS
BUSPIRONE
HYDROXYZINE
ZOLPIDEM
ZALEPLON

20. 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

21. 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

22. 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.

23. 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.

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

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

26. 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

27. 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

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

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

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

31. NONBARBITURATE SEDATIVES
Chloral hydrate
Antihistamine
ethanol

32. 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

34. 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

35. ALCOHOL METAB

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

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

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

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

41. 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.

42. 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

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