Download CNS 2 anxiolytics

CNS DEPRESSANTS
Anti-Anxiety Agents
and Sedative-Hypnotics
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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. 2
• 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.
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CLASSIFICATION
• Barbiturates
• Benzodiazepines
• Are the two major categories of sedativehypnotics
• Other anxiolytic drugs
• Nonbarbiturate sedatives
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BENZODIAZEPINES (BDZs)
• Are the most widely used anxiolytic drugs
• Have replaced barbiturates in the treatment of
anxiety cos are more effective and safer.
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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.
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Benzodiazepines
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DIAZEPAM
ALPRAZOLAM
LORAZEPAM
CLONAZEPAM
FLURAZEPAM
TEMAZEPAM
QUAZEPAM
MIDAZOLAM
ESTAZOLAM
TRIAZOLAM
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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
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• Muscle relaxant: at high doses
• All BDZs have neither anesthetic nor analgesic
property
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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
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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.
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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 14
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
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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
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ADVERSE EFFECTS
• DROWSINESS, CONFUSION
• ATAXIA
• Cognitive impairment
• DEPENDENCE : PSYCHOLOGICAL,
PHYSICAL
WITHDRAWAL :
• ANXIETY, TENSION,CONFUSION,
restlessness, REBOUND INSOMNIA
(Triazolam)
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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.
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OTHER ANXIOLYTIC DRUGS
• BUSPIRONE
• HYDROXYZINE
• ZOLPIDEM
• ZALEPLON
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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
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ZOLPIDEM
• ACTS ON BENZODIAZEPINE RECEPTORS though
not a BDZ.
• HYPNOTIC
• NO ANTI CONVULSANT
• NO MUSCLE RELAXTION
• MINIMAL REBOUND INSOMNIA
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ONSET OF ACTION – FAST
METABOLIZED BY P450 TO INACTIVE COMPOUND
HALF LIFE – SHORT ( 3 HOURS)
SE: NIGHTMARES, GI UPSET, DAYTIME
DROWSINESS
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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.
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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.
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DRUGS
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PHENOBARBITAL – LONG ACTING
PENTOBARBITAL
SECOBARBITAL
Both are short acting
THIOPENTAL – ULTRA SHORT ACTING
( 20 MIN)
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BARBITURATES
MECH OF ACTION :
• Bind to GABA-A receptors potentiating the effect
of GABA by prolonging the duration of chloride
channel opening.
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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
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• 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
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pharmacokinetics
• Readily cross the placenta and can depress the
fetus.
• Are metabolized by the liver except
phenobarbital
• Excreted in urine
• Barbiturate + alcohol = bad combination
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ADVERSE EFFECTS
• Drowsiness
• CNS: Impaired concentration, sluggishness
• HANG OVER: Hynoptic doses
• METABOLISED IN LIVER
• CI : ACUTE INTERMITTENT PORPHYRIA
• DEPENDENCE:
• WITHDRAWAL SEVERE: MAY CAUSE DEATH29
Barbiturate poisoning
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Severe depression of respiration
CVS depression
Shock
Treatment: artificial respiration,gastic lavage,
hemodialysis, alkalinzation of urine.
• No specific barbiturate antagonist available
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NONBARBITURATE SEDATIVES
• Chloral hydrate
• Antihistamine
• ethanol
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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
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ETHANOL
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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
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ALCOHOL METAB
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CNS
CHR. EFFECT
• DEPRESSION, MEMORY LOSS
• RISK FOR SEIZURES
• WERNICKES – KORSAKOFFS
ENCEPHALOPATHY
• Metabolic effects: hypoglycemia, gout,
lactic acidosis
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CVS :
• ACUTE : VASODILATION
• HIGH DOSES : VASOCONSTRICTION IN
HEART
• CHRONIC: MYOCARDIAL DEPRESSION
GIT :
• ACUTE : STIMULATES ACID
• HIGH : DIRECT IRRITATION
• CHRONIC: DIARRHOEA / CONSTIPATION,,
PANCREATITIS
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• LIVER :
• CHR : CIRRHOSIS
• RESPIRATORY DEPRESSION
• CHRONIC :IMPOTENCE, TESTICULAR ATROPHY,
GYNAECOMASTIA
• PREGNANCY : FETAL ALCOHOL SYN.
• LOW IQ, MICROCEPHALY, FACIAL
ABNORMAILITIES.
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continuation
• Elimination: kidney(MC), lung
• Alcohol withdrawal is treated with BDZs
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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.
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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
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Treatment for overdose
• Fomepizole: long acting inhibitor of alcohol
dehydrogenase
• IV Ethanol: for methanol and ethylene glycol
poisoning
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