Pharmacology PPT

2. Drug that
produce a state
of calm or sleep
by reduction of
anxiety, stress,
irritability, or
excitement

3. Drug that
Inducing or
tending to
induce
sleep

4. BASIC PHARMACOLOGY OF
SEDATIVE-HYPNOTICS
• Hypnotic effects involve more pronounced depression
of the central nervous system than sedation, and this
can be achieved with most sedative drugs simply by
increasing the dose.
• Graded dose-dependent depression of central nervous
system function is a characteristic of sedative-
hypnotics.

6. • Barbiturates
• Benzodiazepines
&
Other class of drugs

7. Introduction of Barbiturates
• Barbiturates are derivatives of Barbituric acid.
• Act as central nervous system depressants
• From mild sedation to total anesthesia.
• Barbiturates have now largely been replaced by
benzodiazepines mainly because
benzodiazepines are significantly less
dangerous in overdose.

8. Classification of Barbiturates
A. Long Acting Barbiturates:
> Phenobarbital (Luminal sodium)
> Barbital (Veronal)
> Mephobarbital ( Mebaral)
> Metharbital (Gemonil)
B. Intermediate Acting Barbiturates:
> Amobarbital (Amytal)
> Butarbital (Butisol)

9. C. Short Acting Barbiturates:
> Pentobarbital (Nembutal sodium)
> Secobarbital (Seconal)
D. Ultra – Short Acting Barbiturates
> Thiopental (Penthotal)
> Hexobarbital (Sombulex)
> Methohexital ( Brevital )
> Thiamylal (Surital)

10. Types
Barbituric Acid
Amobarbital Pentobarbital
Short actingIntermediate acting
Long-Acting
Thiopental sodium
Ultra shortacting
Phenobarbital

11.  Barbituric acid is synthesized by a
condensation reaction that results in
the release of H2O (dehydration) and
the heterocyclic pyrimidine
 Further substitution of side chains on
the ring produce the pharmacologically
active barbiturates
Malonic Acid Urea
C2H5—ONa

12. Mechanism of Action
GABA binding site
Barbiturate binding
site
Barbiturates potentiate the effect of GABA at the GABA-A receptor. The GABA-
A receptor is a ligand gated ion channel that allows the flow of Cl through the
membrane in neurons. GABA is the principle neurotransmitter for this receptor
which upon binding causes the channel opening and influx of Cl ions and
creates a negative change in the transmembrane potential.(hyperpolarization)
This makes it an Inhibitory neurotransmitter. As a result neurons becomes
hypoexcitable and so depolarization and action potential cannot occur and
neuronal transmission decrease…

13. Mechanism of Action
Barbiturates also block the AMPA receptor
which is sensitive to glutamate, the excitatory
neurotransmitter. Glutamate performs the
opposite effect from GABA restricting ion flow
and increasing the transmembrane action
potential of the neuron. By blocking this action
Barbiturates serve to increase the duration of
the receptor response to GABA and extend the
depressed condition of the cell.

15. PHARMACOKINETICS:
• Absorption - rapid & complete absorption after oral intake
• Distribution –they are distributed in all body tissues and fluids..
Distribution of barbiturates in body depends on lipid solubility,
degree of protein binding and extend of ionization. barbiturates
redistribute from brain to highly perfused tissues such as
skeletal muscle and subsequently to poorly perfused adipose
tissue
• Metabolism- barbiturates are metabolized in liver by hepatic
microsomal enzymes..
• Excretion- the inactive metabolites are conjugated with
glucoronic acid and are excreted in urine. A small portion of
barbiturates is excreted unchanged in urine

16. PHARMACODYNAMICS
 > Barbiturates depress neuronal activity,
facilitating and prolonging the inhibitory
effects of GABA and glycine
Barbiturates increase the duration of GABA-
mediated chloride ion channel opening

17. •Sedation
• Hypnosis
• Anesthesia
•Anticonvulsant Effects
CNS Effects:
• Depress both respiratory drive & the mechanisms
responsible for the rhythmic character of
respiration
Respiration:
• slight fall of B.P and decrease in heart
rate
Cardiovascular
System

18. Liver
> Combine with
cytochrome 450 &
competitively interfere
with the
biotransformation of a
number of drugs
> Chronic administration
causes a marked increase
in the protein and lipid
content of the hepatic
smooth endoplasmic
reticulum
Kidney
> don’t effect urine
output (hypnotic dosage)
decrease urine output by
decreasing renal blood
flow (anesthetic dosage)

19. Anesthes
ia
• Ultra short acting bbts, such as thiopental, are use
intravenously to induce Anesthesia.
Anticonvul
sant
• Phenobarbital is use in long term management tonic-
clonic seizure, status epilepticus & eclampsia
Anxiety
• Used as mild sedatives to relieve the anxiety, nervous
tension & insomnia. When use as hypnotics they suppress
REM sleep more than other stages

20. Adverse effects
Drowsiness, impaired concentration ,mental
&physical sluggishness. The CNS depressant effects of
barbiturates synergize with those of ethanol
Hypnotic doses of bbts
produces a feelings of tiredness well after patients wakes.
This drug hangover lead to impaired ability to function
normally for many hours after waking

21. As noted previously, bbts induces the
CYP450 system and therefore, may increase the duration
of action of drugs that are metabolized by hepatic
enzymes. Bbts increases the porphyrin synthesis & are
contraindicated to in patients with acute porphyria.
Abrupt withdrawal from bbts
may cause tumors, anxiety, weakness, restlessness,
nausea and vomiting, seizures, delirium & cardiac arrest.
Withdrawal is much more than that associated with opiates
and can result in death

22. • There is no specific antidote for barbiturates
• In past analeptic like metrzol, bemegride etc. have
been used in an attempts to awaken the patients.
• This is dangerous, may precipitate convulsions while
the patients is still comatose- mortality is increased.
• The emphasis now is on keeping the patients alive the
poison has been eliminated.

23. Contraindication
Acute intermittent
porphyria
Liver & kidney disease
Severe pulmonary
insufficiency e.g.
emphysema
Obstructive sleep
apnoea

24. • Bbts induces the metabolism of many drugs and reduce their
effectiveness- warfarin, steroids, tolbutamide, griseofulvin,
chloramphenicol, theophylline.
• Additive action with other CNS depressants alcohol, antihistamines,
opioids etc.
• Sodium valproate increases plasma concentration of phenobarbital

25. • Phenobarbitone competitively inhibits as well as
induces phenytoin and imipramine metabolism:
complex interaction.
• Phenobarbitone decreases absorption of griseofulvin
from GIT.

28. • Benzodiazepines are used primarily in the treatment of
generalized anxiety and panic disorders, as sedative hypnotics,
muscle relaxants, and anticonvulsants
• They largely replaced barbiturates because they're are shown to
have much wider safety margins than barbiturates, thus safer.
• Traditionally they were considered to have a less potential for
addiction and dependence, though this is less true in recent
years.

29. > Alprazolam ( Xanax)
> Chlordiazepoxide ( Librium )
> Chlorazepate ( Tranxene)
> Clonazepam ( Klonopin )
> Diazepam
> Halazepam ( Paxipam )
> Lorazepam ( Ativan )
> Midazolam ( Versed )
> Oxazepam ( Serax )
> Prazepam ( Centrax )
> Temazepam ( Restoril )
> Triazolam ( Halcion )
>Flumazenil

31. Sites of BZDs in brain
• The targets for BZDs in brains are the GABA receptors
• GABA receptors are primarily composed of
o o 2 α subunits (to which GABA binds)
o o 2 β subunits (to which barbiturates bind)
o 1 γ subunit (to which benzodiazepines bind)
• BZDs modulate GABA effects by binding to a specific, high
affinity site located at interface of the
α & γ subunits

32. • Benzodiazepines acting on α2, α3, and/or α5
subunits (but NOT α1) have demonstrated
nonsedative, nonamnesic anxiolytic properties
• Myorelaxant, motor-impairing, and anxiolytic-like
properties thought to be mediated by α2, α3,
and/or α5 subunits

34. Mechanism of Action
Binding of GABA to its receptors triggers an opening of
chloride channel, which leads to an increase in chloride
conductance.
BZDs increase the frequency of channel opening
produces by GABA.
The influx of chloride ions cause a small
hyperpolarization that moves the postsynaptic potential
away from its firing threshold , and ,thus inhibits the
formation of action potentials.

36. Actions
• Reduction of anxiety:-
At low doses BZDs anxiolytic by inhibiting neuronal circuits in limbic system
of brain
• Sedative & hypnotic actions:-
All of BZDs used to teat anxiety have some sedative properties, and some can
produces hypnosis at high doses
• Anterograde amnesia:-
The temporary of memory with the use of benzodiazepam is also mediated by
the α1-GABAa receptors this is also impairs a person’s ability to learn and form
a new memory.

37. • Anticonvulsant:-
Several of BZDs have anticonvulsant activity & some are use
to treat epilepsy & seizures disorder
• Muscle relaxant:-
At high doses, the BZDs relax the spasticity of skeletal
muscle, probably by increasing presynaptic inhibition in spinal
cord, where the α2 GABAa receptors are largely located

38. Location and Therapeutic IndexLocation
of Action
Therapeutic
Effect
Amygdala
Alleviate anxiety, agitation, and fearOrbitofrontal Cortex
Insula
Cerebral Cortex
Mental confusion, amnesia, antiepileptic
actions
Hippocampus
Spinal Cord
Mild muscle-relaxing effects
Cerebellum
Brain Stem
Ventral Tegmental Area
Abuse potential, and psychological
dependence
Nucleus Accumbens

39. Therapeutic uses:-
Muscular
disorder
Amnesia
seizures
• Treat spasms occurs in
muscle strain
• Treat spasticity from
degenerative disorder
I-e multiple sclerosis
• Employed as
premedication for
anxiety-provoking and
unpleasant procedures
I-e endoscopic &
angioplasty
• cause conscious
sedation allowing the
person to be receptive
to instruction during
procedures
• Clonazepam use to treat
certain type of
epilepsy
• Diazepam and lorazepam
use to terminating
grand-mal epileptic
seizures and status
epilepticus

40. • BZDs are effective for the treatment of anxiety symptoms
secondary to panic disorder, generalized anxiety, social
anxiety disorder, performance anxiety, posttraumatic
stress disorder obsessive-compulsive disorder, and
extreme anxiety sometimes encountered with specific
phobias i-e fear of flying.
• BZDs also useful in treating anxiety that accompanies
some form of depression & schizophrenia.

41. •The longer actin agents are preferred
in those patients with anxiety who may
required treatment for prolonged
period of time
•The anti-anxiety effects of BZDs are
less subject to tolerance than the
sedative & hypnotic effect.

42. Precautions
These drugs should not use to alleviate
the normal stress of everyday life
They should be reversed for
continue severe anxiety And then should
only use for short period of time
because of their addiction potential

43. PHARMACOKINETICS:
• Absorption and distribution :-
BZDs are lipophilic they are rapidly and completely
absorbed after oral administration and distribute
throughout the body .

44. 1-3days
Long acting
10-20hours
Intermediate
acting
3-8hours
Short acting

45. • Fate:-
Most BZDs including Chlordiazepoxide and diazepam are
metabolized by the hepatic microsomal system to compound that
are also active.
For these BZDs, the apparent half life of the drug and its
metabolites. The drugs effects are terminated not only by
excretion but also by redistribution.
BZDs are excreted in urine as glucoronides or oxidized
metabolites.
All the BZDs cross placental barrier and may depress the CNS of
newborn if given before birth.
Nursing infants may also. become to the drugs in breast milk

46. • Acute toxicity: Benzodiazepines in
acute overdose are considerably less
dangerous than other sedative-hypnotic
drugs. Cause prolonged sleep, without
serious depression of respiration or
cardiovascular. The availability of an
effective antagonist, flumazenil.

47. • Side-effects during therapeutic
use: drowsiness, confusion, amnesia,
impaired coordination. Main
disadvantages are interaction with
alcohol, long-lasting hangover and the
development of dependence.
• Tolerance and dependence:
induction of hepatic drug-metabolizing
enzymes; a change at the receptor level;

48. Side
Effects
•sedation,
•dizziness,
•weakness, and
•unsteadiness.

49. It is a BZD analog which has little intrinsic activity but
compete with BZD agonist as well as inverse agonists for
BZD receptor and reverses their depressant or stimulant
effects respectively.
Flumazenil abolishes the hypnogien , psychomotor ,
cognitive and EEG effects of BZDs
At high doses it has some weak BZD agonist- like as well
as inverse agonist-like activity in animal models but these
are not of clinical significance

50. ♦ Flumazenil is absorbed orally; oral bioavailability is 16%
♦ But not used orally
♦ On I.V injection action of flumazenil starts in seconds and
lasts for 1-2 hrs.
♦ Elimination:-
♦ Elimination t12 is 1 hour due to rapid metabolism

51. 1. To reverse BZD anaesthesia :- patient anaesthetized /sedated with
BZD wake up, get oriented and regain within 1 min of an I.V injection
of 0.3-1 mg of flumazenil. Resedation generally occurs after 1-2 hrs.;
supplemental doses of flumazenil may be given.
2. BZD overdose:- Majority of patients of BZDs overdose require only
supportive measures like patent airway, cardiac and renal function,
etc. In addition, flumazenil 0.2 mg/min may be injected I.V till patient
regain consciousness. Practically all patients intoxicated with a BZD
alone response within 5 mins. However reversal respiratory depression
is incomplete