GROUP 6
Clinical Pharmacology 2

Members
i. CALEB WANYONYI 21-2220
ii. AKAL MORRIS 21-2668
iii. TONY BARAKA 21-2114
iv. ASNATH MAKORI 21-2853
v. SOFIA MURIUNGI 21-2755
vi. NEDDY CHELANGAT 21-2315
vii.VINCENT KIBUNGEI 21-2435
viii.TRACY MURANDE 22-0173
ix. DAVID MACHUKA. 21-2325
x. HADEN CHWEYA 21-2340

Stages of sleep
Stage 1 (2-5%)
REM (Ø
&αwaves)
Stage 2
Non REM
(67-75
STAGE 3
DEEP
SLEEP
STAGE 4
DEEP
SLEEP

Pharmacokinetics
Route: oral
Absorption: lipid-soluble and are absorbed well from
the gastrointestinal tract
Distribution: wide and crosses BBB
Metabolism: liver
Elimination: urine

Pharmacodynamics
The CNS effects of most sedative-hypnotics depend on
dose.
These effects range from sedation and relief of anxiety
(anxiolysis), through hypnosis (facilitation of sleep), to
anesthesia and coma.
Depressant effects are additive when 2 or more drugs are
given together.
The steepness of the dose–response curve varies among
drug groups; those with flatter curves, such as
benzodiazepines and the newer hypnotics (eg, zolpidem),
are safer for clinical use.

Mode of Action
Barbiturates
Bind to the GABA-A receptor and increase the duration of chloride ion
channel opening, leading to neuronal inhibition.
Benzodiazepines
Benzodiazepines bind to a specific site on the GABA-A receptor and
enhance the affinity of GABA for the receptor, leading to increased
chloride ion channel opening and neuronal inhibition.
Non-benzodiazepine hypnotics also enhance the activity of the GABA
receptor, but through a different mechanism.

Long-acting and sshort-acting
benzodiazepines
a) Short-acting benzodiazepines
Short-acting benzodiazepines have a shorter half-life. This means that the
drugs are processed and leave the body more quickly.
Short-acting drugs have a higher risk of withdrawal symptoms. This is because
the body has less time to adapt to working without the drug once you stop
taking it.
b) Long-acting benzodiazepines
They have a longer half-life. This means that the drugs are processed by the
body more slowly and take longer to leave the body.

Classification of benzodiazepines
Short acting (3-5hours)
 Triazolam
Intermediate (6-24hrs)
 Alprazolam
 Lorazepam
 Estazolam
 Oxazepam
 Temazepam
Long acting (24-72hrs)
Chlorazepate
Chlordiazepoxide
Diazepam
Flurazepam
Quazepam
Prazepam
Nitrazepam

MoA (benzodiazepines)
GABA is the transmitter most associated with inhibition in the
CNS and the GABA receptor mediates this effect.
Receptors for benzodiazepines are located on the GABAA
receptor molecule and thus are present in many brain regions,
including the thalamus, limbic structures, and the cerebral cortex
The drug binds to GABA-A (gamma-aminobutric Acid) receptors
and increase frequency of Chloride channel opening.
Increasing chloride flow into neurons hence hyperplorasation
therefore inhibiting propagation of AP

Pharmacokinetics
Route: oral, IM (SLOW)
Absorption: Via GIT
Distribution: Wide
Metabolism: liver as they bind to plasma protein
Excretion: Kidney

Indications

Adverse Effects
•Ataxia
•Hangover
•Tolerance
•Physical and psychological dependence
•Withdrawal Symptoms (insomnia, anorexia, agitation, tremors,
Convulsions)
•Drowsiness & Dizziness (common)

Drug Interaction
•Synergistic effects with CNS depressant
•Enzyme modulators :
Rifampicin (decrease ½ life)
Cimetidine (increase ½ life)
*N/B These drugs are Pregnancy risk category D
(studies in pregnant women have demonstrated a risk to
the fetus; potential benefits of the drug may outweigh the
risks)

2. Barbiturates
•Derivatives of barbutric acid thus
the name
CLASSIFICATION
Long acting (6-12hours)
Mephobarbitone
Phenobarbitone
Intermediate acting (3-6hrs)
Amobarbitone
Aprobarbitone
Butabarbitone
Short acting <3hrs
Hexabarbitone
Pentobarbitone
Secobarbitone
Ultra-Sound Acting<15-20mins
Thiopentone
Methohexitone

MoA
Act to GABA but does not bind to BZD (α and ϒ) but binds to
another site (α and β ) on the same macromolecular complex to
exert GABA facilitatory action.
They also enhance BZD binding to their site.
At high conc they increase chloride ions conductance and
inhibit Calcium ions dependent release of neurotransmitter
They depress glutamate induced neuronal depolarization thr
AMPA receptors.

Pharmacokinetics
Route: Oral
Absorption: via GIT
Distribution: wide ( from CNS to Skeletal muscles)
Metabolism: Liver by oxidation, conjugation, dealkylation
Excretion: Kidney

Indications
Epilepsy except for phenobarbitone and anesthesia
thiopentone
Adjuvant in psychosomatic disorders

Adverse effects
Hangover
Tolerance
Idiosyncrasy (untoward reactions to drugs that occur in a
small fraction of patients and have no obvious relationship
to dose or duration of therapy)
Hypersensitivity
Mental Confusion
*It has no specific antidote

INDICATIONS (generally)
Sedatives
i. Sedatives are used for a variety of indications, including anxiety,
insomnia, and seizure disorders. Barbiturates are used primarily for
anesthesia induction and maintenance, but are also used as
anticonvulsants. Benzodiazepines are used for anxiety, insomnia,
seizure disorders, and muscle relaxation. Non-benzodiazepine
hypnotics are used primarily for insomnia.
Hypnotics
i. Hypnotics are primarily used to treat insomnia, sleep disturbances,
and other sleep disorders. They are also used in certain medical
procedures that require sedation or anesthesia.

Toxicity
i. Psychomotor dysfunction
ii. Additive CNS depression
iii.Overdose

Drug interaction
diazepam, flurazepam + benzodiazepines=
Excessive Sedation

ATYPICAL SEDATIVE-HYPNOTICS
Buspirone
MoA
•The drug interacts with the 5-HT1A subclass of brain serotonin receptors
as a partial agonist, but the precise mechanism of its anxiolytic effect is
unknown
•Pharmacokinetics
•metabolized by CYP3A4, and its plasma levels are markedly increased by
drugs such as erythromycin and ketoconazole
•Adverse effects; tachycardia, paresthesias, pupillary constriction, and
gastrointestinal distress
 Buspirone is safe in pregnancy

Orexin Antagonists
•Orexin is a peptide found in the hypothalamus and is involved in
wakefulness
•Suvorexant, an antagonist at OX1R and OX2R orexin receptors,
has hypnotic properties and is approved for the treatment of
insomnia.

Miscellaneous
(Non-benzodiazepines hypnotics)
1. Zopiclone
Agonist subtype of BZD receptors involved in hypnotics action.
Used for insomnia (<2weeks)
Side effects: metallic taste, dry mouth, mild dependence,
impaired judgement

2. paraldehyde
It is colourless, transparent, pungent and inflammable liquid.
Given Rectally, IV, IM,Orally
Used in epilepsy in children
*Others Melatonin- hormone from pineal gland that improve quality of
sleep.
*Ramelteon-melatonin agonist

THANK YOU FOR YOUR ATTENTION
The good physician treats the disease; the great
physician treats the patient who has the disease.
William Osler

References
1. Kartzung, B. G. & Trevor, A. (2015). Basic and Clinical Pharmacology.
McGraw-Hill; (13thed.) ISBN: 13-9780071825054; 10: 0071825053

QUESTIONS????
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Prepared by: Akal Lobenyo Morris