Download Sedative-Hypnotics

 Sedative is a substance that produces a calming effect by reducing
irritability or excitement without inducing sleep (though drowsiness
may be produced).
 Hypnotic (“sleeping pills”) is a substance that induces or maintains
sleep and is used in the treatment of insomnia (sleeplessness), or
surgical anesthesia.
 Hypnotic at lower dose may act as sedative.
 Because these two functions frequently overlap, they are often referred
to collectively as sedative-hypnotic drugs.
 Anxiolytic (“antipanic” or minor tranquilizer) is a medication that
inhibits anxiety.
Anxiolytic medications are used for the treatment of anxiety/ anxiety
disorders and its related psychological and physical symptoms.
Types of sedatives
 Herbal sedatives:
 Chamomile
 Mentha (also known as ”mint”)
 Catnip / catmint
 Kava (Piper methysticum)
 Valerian
 Leonurus (motherwort)
 Cannabis
 Passiflora (passionflower or wild apricot)
 Validol (menthyl ester of isovaleric acid)
 Barbiturates
 Benzodiazepines
 Nonbenzodiazepine "Z-drugs" sedatives
 Antihistamines (1 generation)
Therapeutic use
 To dull the patient's anxiety related to
painful or anxiety-provoking procedures.
 They are commonly given to patients before
highly uncomfortable and invasive
procedures like cardiac catheterization,
colonoscopy or MRI.
 They increase tractability and compliance of
children or troublesome or demanding
patients.
ADR:
 Drowsiness
 Sedative dependence
 Misuse
 Dangers of combining sedatives and alcohol
 Worsening of Psychiatric Symptoms
Hypnotics
CLASSIFICATION
I class -Barbiturates:
 Long acting Phenobarbital
 Short acting Pentobarbital, amobarbital
II class - Benzodiazepines:
 Diazepam, Flurazepam, Lorazepam,Nitrazepam, Oxazepam,
Clonazepam, Alprazolam, Triazolam
III class - Non-benzodiazepines ("Z-drugs” hypnotics):
 Zopiclone, Zolpidem
 Antihistaminics (promethazine, diphenhydramine)
 Neuroleptic/antidepressants (chlorpromazine, amitriptyline)
BARBITURATES
 Barbiturates have been popular hypnotics and
sedatives of the last century upto 1960s, but are not
used now to promote sleep or to calm patients.
 They are the prototype of CNS depressants.
They are effective as:
 anxiolytics,
 hypnotics,
 anticonvulsants.
They are still used:
 in general anesthesia,
 for epilepsy,
 For (where legal) assisted suicide and euthanasia
PHARMACOLOGICAL ACTIONS
CNS
 Depress all areas of the CNS.
 Barbiturates produce dose-dependent effects: sedation → sleep
→ anaesthesia → coma.
 Shortening the time taken to fall asleep and increases sleep
duration.
 REM-stage sleep are decreased → REM-NREM sleep cycle is
disrupted → Hangover (dizziness, distortions of mood,
irritability and lethargy) occur in the morning after → after a
few nights of use → a rebound increase in REM sleep →
nightmares
 At daytime can produce drowsiness, reduction in anxiety and
excitability, impair learning, short-term memory and
judgement.
Mechanism of action
 Barbiturates bind to receptor on the macromolecular
complex → exert the GABA (gamma-Aminobutyric acid)
facilitatory action → inhibitory action on the brain
GABA-benzodiazepine-barbiturate receptor
The BZD- receptor and barbiturate receptor modulate GABAreceptor → channel opening → facilitates GABA
PHARMACOLOGICAL ACTIONS
 Respiration is depressed by relatively higher doses.
 CVS a slight decrease in BP and heart rate.
 Smooth muscles -Tone and motility of bowel is
decreased slightly
 Barbiturates induce several hepatic microsomal
enzymes and increase the rate of their own
metabolism as well as that of many other drugs.
ADVERSE EFFECTS
 Hangover
 Mental confusion, impaired performance and traffic
accidents may occur.
 Idiosyncrasy
 Hypersensitivity (Rashes, swelling of eyelids, lips, etc.)
 Tolerance and dependence
Psychological as well as physical dependence occurs and
barbiturates have considerable abuse liability. This is one
of the major disadvantages. Withdrawal symptoms are—
excitement, hallucinations, delirium, convulsions; deaths
have occurred.
Acute barbiturate poisoning
 Mostly suicidal, sometimes accidental.
 Manifestations are due to excessive CNS depression— patient is
flabby and comatose with shallow and failing respiration, fall in
BP and cardiovascular collapse, renal shut down, pulmonary
complications, bullous eruptions.
 Treatment
1. Activated charcoal in the stomach to prevent absorption
2. Supportive measures: such as, patent airway, assisted respiration,
oxygen, maintenance of blood volume by fluid infusion and use
of vasopressors—dopamine may be preferred for its renal
vasodilating action.
3. Diuretics
4. Haemodialysis and haemoperfusion (through a column of
activated charcoal or other adsorbants) are highly effective
 There is no specific antidote for barbiturates.
 The emphasis now is on keeping the patient alive till the poison
has been eliminated.
BENZODIAZEPINES (BZDs)
 This class has replaced barbiturates as
hypnotic and sedative as well
1) BZDs produce a lower degree of
neuronal depression than barbiturates.
They have a high therapeutic index.
2) Hypnotic doses do not affect respiration
or cardiovascular functions.
3) BZDs have no action on other body
systems.
4) BZDs cause less distortion of sleep
architecture; rebound phenomena on
discontinuation of regular use are less
marked.
5) They have lower abuse liability:
tolerance is mild, psychological and
physical dependence, drug seeking and
withdrawal syndrome are less marked.
6) A specific BZD antagonist flumazenil is
available which can be used in case of
poisoning.
BZDs
Antianxiety: all
Sleep-problems: all
Muscle relaxant: Clonazepam and diazepam
Anticonvulsant: Clonazepam, diazepam, nitrazepam, lorazepam and flurazepam
Analgesia: only diazepam i.v. (but not others)
NON-BENZODIAZEPINE HYPNOTICS
 This lately developed group of
hypnotics are chemically different
from BZDs, but act as agonists on a
specific subset of BZD receptors
 The non-BZD produce only
hypnotic-amnesic action (not
antianxiety, muscle relaxant and
anticonvulsant effects).
 They have lower abuse potential
than BZDs.
 They are being preferred over BZDs
for the treatment of insomnia.
Z-drugs




Zopiclone and Zolpidem
Not to disturb sleep architecture → not next morning
impairment.
Are indicated for short term (< 2 weeks) treatment of
insomnia.
Low abuse potential
Side effects are metallic or bitter after-taste, impaired
judgement and alertness, psychological disturbances, dry
mouth.
ANTIANXIETY DRUGS
Anxiety
 It is an emotional state, unpleasant in
nature, associated with uneasiness,
discomfort and concern or fear about
some defined or undefined future
threat.
 Treatment is needed when it is
disproportionate to the situation and
excessive.
Cardiac neurosis (unfounded fear of heart disease—
palpitation, functional precordial pain);
social anxiety (fear of being observed and evaluated
by others);
obsessive-compulsive disorder (OCD),
post-traumatic stress disorder and various forms of
phobias are some specific types of anxiety disorders.
Antianxiety drugs
 These are mild CNS depressants, which are
aimed to control the symptoms of
anxiety, produce a restful state of mind
without interfering with normal mental or
physical functions.
 The anxiolytics are close to sedative-
hypnotics.
They:
 Have anticonvulsant property.
 Produce physical dependence and carry
abuse liability.
CLASSIFICATION
1. Benzodiazepines
 Diazepam
 Chlordiazepoxide
 Oxazepam
 Lorazepam,
 Alprazolam
2. Azapirones
 Buspirone,
 Gepirone,
 Ispapirone
3. Sedative antihistaminic
 Hydroxyzine
4. β blocker
 Propranolol
5. Antidepressants are effective in OCD, phobias, panic and many
types of severe generalized anxiety disorders.
BENZODIAZEPINES
 BZDs have a strong action on anxiety relief at low doses
without producing significant CNS depression.
 They are selective for the limbic system and have proven
clinically both quality and quantity of improvement in
anxiety and stress-related symptoms.
 Because anxiety is a common complaint and is a part of most
physical and mental illness, and because the BZDs—
 have little effect on other body systems
 have lower dependence producing liability than
barbiturates and other sedatives;
 withdrawal syndrome is milder and delayed due to
their long half lives
 are relatively safe even in gross overdosage,
they are presently one of the widely used class of drugs.
Azapirones
!
!
!
!
!
Buspirone, Gepirone, Ispapirone
Do not produce sedation
Have no muscle relaxant or anticonvulsant activity.
Do not interact with BZD receptor or modify GABA-ergic
transmission.
Do not produce tolerance or physical dependence.
Do not suppress BZD or barbiturate withdrawal syndrome.
 Relieve only mild-to-moderate anxiety, but are ineffective in
severe cases (panic reaction and OCD)
 Side effects are minor: dizziness, nausea, headache, light-
headedness, rarely excitement.
 They are a non-sedating alternative to BZDs for chronic treatment of mild forms
of generalized anxiety (BZDs are not suitable for long-term therapy).
Hydroxyzine
 An H1 antihistaminic with:
 sedative,
 antiemetic,
 antimuscarinic
 and spasmolytic properties.
 It is claimed to have selective anxiolytic action, but the
accompanying sedation is quite marked.
 Hydroxyzine may be used in reactive anxiety or that
associated with marked autonomic symptoms.
 Due to antihistaminic and sedative property, it is useful in
pruritus and urticaria(hives, rash).
β Blockers
 Many symptoms of anxiety (palpitation, rise in BP, shaking,
tremor, gastrointestinal hurrying, etc.) are due to sympathetic
over-activity, and these symptoms reinforce anxiety.
 Propranolol and other nonselective β blockers help anxious
patients troubled by these symptoms, by cutting the vicious
cycle and provide symptomatic relief.
 They do not affect the psychological symptoms such as worry,
tension and fear, but are valuable in acutely stressful situations
(examination fear, unaccustomed public appearance, etc.).
 They may be used for performance/situational anxiety or as
adjuvant to BZDs.
Antidepressants
 The SSRIs and SNRIs are now extensively used in most
forms of chronic anxiety disorders, but are not good
for acute anxiety→ can be combined with BZDs.
 The SSRIs are now drugs of choice for social anxiety,
OCD, eating disorders and PTSD in which BZDs,
though effective, carry abuse potential on long-term
use.
Epilepsy
 Brief episodes (seizures) of loss or disturbance of
consciousness, with or without characteristic body movements
(convulsions), sensory or psychiatric phenomena.
 These episodes are unpredictable and their frequency is highly
variable.
 Epilepsy has a focal origin in the brain
Types of epilepsy
I. Generalised seizures
1. Generalised tonic-clonic seizures (major epilepsy, grand mal):
commonest, lasts 1–2 min.
 The usual sequence is aura—cry—unconsciousness—tonic spasm of all
body muscles—clonic jerking followed by prolonged sleep and
depression of all CNS functions.
2. Absence seizures (minor epilepsy, petit mal): lasts about 1/2 min.
 Momentary loss of consciousness, patient apparently freezes and stares
in one direction, no muscular component or little bilateral jerking.
3. Atonic seizures (Akinetic epilepsy): Unconsciousness with relaxation of all
muscles due to excessive inhibitory discharges. Patient may fall.
4. Myoclonic seizures: Shock-like momentary contraction of muscles of a
limb or the whole body.
II. Partial seizures
Focal epilepsy: lasts 1/2–1 min.
 Often secondary. Convulsions are confined to a group of muscles or
localized sensory disturbance depending on the area of cortex involved in
the seizure, without loss of consciousness
III. Status epilepticus
 In status epilepticus, two or more seizures occur without recovery of full
consciousness in between episodes. Status epilepticus is life threatening
and requires emergency treatment
CLASSIFICATION
 Na-channel blockers :
— phenytoin;
— carbamazepine;
 GABA-ergic system stimulants:
— barbiturates: (phenobarbital)
— benzodiazepines:(diazepam; clonazepam; lorazepam)
— vigabatrin;
— valproic acid;
— topiramate.
 Excitatory amino acids inhibitors:
—lamotrigine
 Ca2+ channel blockers:
— ethosuximide.
Major mechanisms of anticonvulsant action
Effect on membrane potential → synaptic transmission blocked → stabilizing
influence on neuronal membrane → prevents repetitive detonation of normal brain
cells during ‘depolarization shift’ that occurs in epileptic patients
Choice of antiseizure drugs
Carbamazepine
Uses
 Grand mal: it is the most effective drug for CPS and
also the most commonly used drug for generalised
tonic-clonic seizures
 Trigeminal and related neuralgias: Carbamazepine is
the drug of choice. Carbamazepine is not an analgesic,
but has a specific action (almost diagnostic) in these
neuralgias.
 Manic depressive illness and acute mania: as an
alternative to lithium
ANTIEPILEPTIC DRUGS
Valproic acid (Sodium valproate)
 is the drug of choice for absence seizures
 It is an alternative/adjuvant drug for GTCS.
 Myoclonic and atonic seizures—control is often incomplete, but
valproate is the drug of choice
Ethosuximide
 Clinically it is effective only in absence seizures (drug of 2nd choice).
Phenytoin
 is a first line antiepileptic drug, but less commonly used now because
side effects are frequent and marginal overdose causes steep rise in
plasma concentration, producing neurotoxicity.
 Indications are: Generalized tonic-clonic, simple and complex
partial seizures.
 It is ineffective in absence seizures.
Adverse effects
 Hypersensitivity reactions
 Haematotoxicity (agranulocytosis,aplastic anaemia)
 Neurotoxicity (Ataxia, vertigo, diplopia, nystagmus
,drowsiness, behavioral alterations, mental confusion,
hallucinations, disorientation and rigidity)
 Teratogenicity (spina bifida and other neural tube
defects in the offspring)
Status epilepticus
 When seizure activity occurs for > 5
min (previous definitions used a 30-minute time limit), or two
or more seizures occur without
recovery of consciousness, the
condition is called status epilepticus.
 Recurrent tonic-clonic convulsions
without recovery of consciousness in
between is an emergency;
 Fits (attacks) have to be controlled
as quickly as possible to prevent
death and permanent brain damage.
 An ambulance should be called for
seizures lasting longer than 5
minutes.
Status epilepticus treatments
1) BZDs (IV or IM)
 Benzodiazepines are the preferred initial treatment after
which typically phenytoin is given.
 IV- lorazepam, clonazepam, diazepam
 IM- midazolam appears to be a reasonable option
especially in those who are not in hospital.
2) Barbiturates (Thiopental or pentobarbital) IV
 These are used to induce a “barbituric coma” if the seizures
have to be stopped immediately
3) Phenytoin (IV) is another first-line therapy.
 Because it takes 15–30 minutes to work, a BZDs or
barbiturate is often coadministered with phenytoin.
4) General anaesthesia(fail to respond to drugs above)