Pharmacology document discusses central nervous system (CNS) depressants like alcohols, barbiturates, benzodiazepines, and newer non-benzodiazepine hypnotics. It describes their mechanisms of action, pharmacological effects on various body systems, classifications, and examples. Key points include ethanol and methanol acting as CNS depressants; barbiturates formerly used as hypnotics and sedatives but now replaced due to side effects; benzodiazepines having lower CNS depression than barbiturates; and newer non-benzodiazepine hypnotics like zolpidem and zaleplon acting on GABA receptors with improved

1. Pharmacology
By-
Dr. Mrunal R. Akre

2. CNS Depressant

3.  ETHYL ALCOHOL (Ethanol)-
 Mythyl Alcohol (Methanol)-
 Alcohols are hydroxy derivatives of aliphatic hydrocarbons. When
unqualified, ‘alcohol’ refers to ethyl alcohol or ethanol.
 PHARMACOLOGICAL ACTIONS
◦ 1. Local actions
 Ethanol is a mild rubefacient and counterirritant when rubbed on the skin. By
evaporation it produces cooling.
 Applied to delicate skin (scrotum) or mucous membranes it produces irritation and
burning sensation.
 Concentrated alcohol (spirit) should not be applied in the mouth, nose, etc. Injected
s.c. it causes intense pain, inflammation and necrosis followed by fibrosis. Injected
around a nerve it produces permanent damage.
◦ CNS
 Alcohol is a neuronal depressant.
 Since the highest areas are most easily deranged and these are primarily inhibitory—
apparent excitation and euphoria are experienced at lower plasma concentrations
(30–60 mg/dl).
 Hesitation, caution, self-criticism and restraint are lost first.
 Mood and feelings are altered; anxiety may be allayed.
 With increasing concentration (80– 150 mg/dl) mental clouding, disorganization of
thought, impairment of attention, memory and other faculties, alteration of gait and
perception and drowsiness supervene.
 At 150–200 mg/dl the person is sloppy, ataxic and drunk, ‘blackouts’ occur; 200–300
mg/dl result in stupor and above this unconsciousness prevails, medullary centres are
paralysed and death may occur.
 Though, alcohol can produce anaesthesia, margin of safety is narrow.

4.  CVS
◦ The effects are dependent on dose.
 Small doses: produce only cutaneous (especially on the face) and gastric vasodilatation. BP is not affected.
 Moderate doses: cause tachycardia and a mild rise in BP due to increased muscular activity and sympathetic
stimulation.
 Large doses: cause direct myocardial as well as vasomotor centre depression and there is fall in BP.
 Blood
◦ Regular intake of small to moderate amounts of alcohol (1–2 drinks) has been found to raise HDL-
cholesterol levels and decrease LDL oxidation.
 Body temperature
◦ Alcohol is reputed to combat cold.
 GIT
◦ Alcoholic beverages have variable effect on gastric secretion depending on the beverage itself
 Liver
◦ Neither brief alcohol intoxication nor chronic intake of small-to-moderate amounts cause significant
liver damage, provided adequate nutrition is maintained.
 Respiration
◦ Brandy or whiskey are reputed as respiratory stimulants in collapse. They irritate buccal and
pharyngeal mucosa which may transiently stimulate respiration reflexly.
 Skeletal muscle
◦ Alcohol produces little direct effect. Fatigue is allayed by small doses, but muscle work is increased or
decreased depending on the predominating central effect.
 Kidney
◦ Diuresis is often noticed after alcohol intake.
 Endocrine effects
◦ Moderate amounts of alcohol increase Adr release which can cause hyperglycaemia and other
sympathetic effects.

5. Mechanism of action
 Alcohol was believed to produce CNS depression by
a generalized membrane action altering the state of
membrane lipids.
 However, lately specific effect on multiple receptor
operated and voltage gated ion channels/ other
critical proteins has been demonstrated at
concentrations attained during moderate drinking.
 Thus, several neurohumoral systems are
concurrently affected producing a complex pattern of
action quite different from that produced by other
depressants like barbiturates and benzodiazepines,
which predominantly facilitate GABAA receptor
mediated Cl¯channel opening. Alcohol has been
shown to enhance GABA release at GABAA sites in
the brain.
 It also inhibits NMDA and kainate type of excitatory
amino acid receptors (operating through cation
channels)

6. Sedative-Hypnotics

7. Sedative-Hypnotics
 Sedative
◦ A drug that subdues excitement and calms the
subject without inducing sleep, though drowsiness
may be produced.
◦ Sedation refers to decreased responsiveness to any
level of stimulation; is associated with some decrease
in motor activity and ideation.
 Hypnotic
◦ A drug that induces and/or maintains sleep, similar to
normal arousable sleep.
◦ This is not to be confused with ‘hypnosis’ meaning a
trans-like state in which the subject becomes passive
and highly suggestible.
 The sedatives and hypnotics are more or less
global CNS depressants with somewhat differing
time-action and dose-action relationships.

8. CLASSIFICATION
 Barbiturates
◦ Long acting
 Phenobarbitone
◦ Short acting
 Butobarbitone, Pentobarbitone
◦ Ultra-short acting
 Thiopentone, Methohexitone
 Benzodiazepines
◦ Hypnotic
 Diazepam, Flurazepam , Nitrazepam , Alprazolam, Temazepam,
Triazolam
◦ Antianxiety
 Diazepam, Chlordiazepoxide , Oxazepam , Lorazepam,
Alprazolam
◦ Anticonvulsant
 Diazepam, Clonazepam, Lorazepam, Clobazam
 Newer nonbenzodiazepine hypnotics
◦ Zopiclone, Zolpidem, Zaleplon

9. 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.
 PHARMACOLOGICAL ACTIONS
◦ Barbiturates are general
◦ CNS - Barbiturates produce dose-dependent effects:
◦ sedation → sleep → anaesthesia → coma depressants.
◦ Other systems
 Respiration is depressed by relatively higher doses. Neurogenic,
hypercapneic and hypoxic drives to respiratory centre are depressed in
succession. Barbiturates donot have selective antitussive action.
 CVS Hypnotic doses of barbiturates produce a slight decrease in BP and
heart rate.
 Skeletal muscle Hypnotic doses have little effect but anaesthetic doses
reduce muscle contraction by action on neuromuscular junction.
 Smooth muscles Tone and motility of bowel is decreased slightly by
hypnotic doses; more profoundly during intoxication.
 Kidney Barbiturates tend to reduce urine flow by decreasing BP and
increasing ADH release.

10.  PHARMACOKINETICS
◦ Barbiturates are well absorbed from the g.i. tract.
◦ They are widely distributed in the body.
◦ The rate of entry into CNS is dependent on lipid solubility.
 USES
◦ Except for phenobarbitone in epilepsy and thiopentone in
anaesthesia no other barbiturate is used now.
 ADVERSE EFFECTS
◦ Side effects -Hangover , Mental confusion, impaired
performance and traffic accidents may occur.
◦ Idiosyncrasy -Excitement.
◦ Hypersensitivity- Rashes, swelling of eyelids, lips, etc.
◦ Tolerance and dependence -Both cellular and
pharmacokinetic (due to enzyme induction) tolerance
develops on repeated use. There is partial cross
tolerance with other CNS depressants. Psychological as
well as physical dependence occurs and barbiturates
have considerable abuse liability.
◦ Acute barbiturate poisoning Mostly suicidal,
sometimes accidental.

11. BENZODIAZEPINES (BZDs)
 Chlordiazepoxide and diazepam were
introduced around 1960 as antianxiety drugs.
 BZDs produce a lower degree of neuronal
depression than barbiturates.
 Hypnotic doses do not affect respiration or
cardiovascular functions. Higher doses produce
mild respiratory depression and hypotension.
 BZDs have practically no action on other body
systems
 BZDs cause less distortion of sleep architecture.
 BZDs do not alter disposition of other drugs.
They have lower abuse liability: tolerance is
mild, psychological and physical dependence,
drug seeking and withdrawal syndrome are less
marked.

12.  Site and mechanism of action
◦ Benzodiazepines act preferentially on
midbrain ascending reticular formation
(which maintains wakefulness) and on
limbic system (thought and mental
functions). Muscle relaxation is produced by
a primary medullary site of action and
ataxia is due to action on cerebellum.
 PHARMACOKINETICS
◦ There are marked pharmacokinetic
differences among BZDs because they
differ in lipidsolubility by > 50 fold. These
differences are important factors governing
their choice for different uses. Oral
absorption of some is rapid while that of
others is slow.

13.  Flurazepam –
◦ There is slow elimination of parent drug or active Metabolite
◦ Produces an active metabolite which has a long t½.
◦ It is suitable for patients who have frequent nocturnal awakenings and
in whom some day time sedation is acceptable.
◦ NINDRAL, FLURAZ 15 mg cap.
 Diazepam –
◦ Relatively slow elimination but marked redistribution
◦ It is the oldest and all purpose BZD, used as anxiolytic, hypnotic,
muscle relaxant, premedicant, anaesthetic and for emergency control
of seizures due to its broad spectrum activity.
◦ VALIUM 2, 5, 10 mg tab., 10 mg/2 ml inj., CALMPOSE 2.5, 5, 10 mg
tab, 2 mg/5 ml syr, 10 mg/2 ml inj, PLACIDOX 2, 5, 10 mg tab, 10 mg/2
ml inj.
 Nitrazepam –
◦ Dose to dose equipotent as diazepam.
◦ SEDAMON, HYPNOTEX, NITRAVET 5 mg tab., 5, 10 mg cap.
 Alprazolam –
◦ It has Relatively rapid elimination and marked redistribution. The
primary indication of this potent and intermediate acting BZD is
anxiety disorder, but it is also being employed as night-time hypnotic
with few residual effects the next day

14.  ADVERSE EFFECTS
◦ Benzodiazepines are relatively safe drugs.
◦ Side effects of hypnotic doses are dizziness,
vertigo, ataxia, disorientation, amnesia,
prolongation of reaction time—impairment of
psychomotor skills (should not drive).

15. 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.
 Zopiclone –
◦ This is the first of the non-BZD hypnotics, which acts as an agonist at a subtype of
BZD receptor involved in the hypnotic action.
◦ TM- ZOPITRAN, ZOPICON, ZOLIUM, 7.5 mg tab, one tab at bedtime for not more
than 2–4 weeks (elderly 3.75 mg).
◦ Eszopiclone - The active (S) enantiomer of zopiclone has recently been approved.
 Zolpidem –
◦ This structurally non-BZD, but selective BZD receptor agonist has pronounced
hypnotic effect.
◦ Sleep latency is shortened, sleep duration is prolonged in insomniacs, but
anticonvulsant, muscle relaxant and antianxiety effects are not evident.
◦ Dose: 5–10 mg (max 20 mg) at bedtime; ½ dose in elderly and liver disease
patients.
◦ TM- NITREST, ZOLDEM, DEM 5, 10 mg tabs.
 Zaleplon –
 This is the shortest acting of the newer non-BZD hypnotics that selectively act on a
subset of BZD receptors containing the α1 subunit which appear to mediate the
hypnotic action.
◦ Dose: 5–10 mg (max 20 mg) at bed time.
◦ ZAPLON, ZALEP, ZASO 5, 10 mg tabs.

16. BENZODIAZEPINE
ANTAGONIST
 Flumazenil-
◦ It is a BZD analogue which has little intrinsic activity
(practically no effect on normal subjects), but competes
with BZD agonists as well as inverse agonists for the
BZD receptor and reverses their depressant or stimulant
effects respectively.
 Uses
◦ To reverse BZD anaesthesia Patients
anaesthetized/sedated with a BZD wakeup, get oriented
and regain motor control within 1 min of an i.v. injection
of 0.3–1 mg of flumazenil.
◦ BZD overdose Majority of patients of BZD overdose
require only supportive measures like patent airway,
maintenance of BP, cardiac and renal function (by fluid
transfusion, etc.)
 Adverse effects
◦ Flumazenil is safe and well tolerated.