PHARMACOLOGY OF ANXIOLYTICS/SEDATIVES-

HYPNOTICS

Death

Coma

Hypnosis

sedation

Amnesia

Awake
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• Anxiolytics :a drug which reduces anxiety and
causes calm and quietness in the patient

• Sedatives: a drug that decrease activity and

calms the patient

• Hypnotics: a drug that produces drowsiness

and facilitates the onset and maintenance of a
state of sleep that resembles natural sleep
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The GABAergic system
• GABA receptors : control fear and anxiety due
to over-excitation of neurons
• Major inhibitory neurotransmission in the
brain (specially cortex, hippocampus)
Barbiturates and BDZ potentiate the effect of
GABA on the GABAA receptor
 Sedative Hypnotics

Sedative / hypnotics
A. Effective sedative
– Reduces anxiety without inducing sleep
– Slight decrease on motor activity
– CNS depression should be minimal
– Quicker onset, shorter duration

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 Sedative Hypnotics

B. Effective Hypnotic
– produce drowsiness
– encourage the onset and maintenance of
a state of sleep
– pronounced depression of the central
nervous system
– Graded dose-dependent depression of
CNS function is a characteristic of most
sedative-hypnotics

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 Sedative Hypnotics

• Hypnotics
at lower dose may act as sedative and
at higher dose can produce general anesthesia

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1.Barbiturates:

 Produce dose dependent effect

 All derivatives of Barbituric acid

• Barbituric acid was first created in 1864.

• It was a combination of urea from animals and malonic acid

from apples.

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•Was first used to put dogs to sleep.

•Phenobarbital was soon discovered and marketed.

•Caused the death of many celebrities at earlier times

•Used by the Nazis during WWII for euthanasia

•Prescribed as sedatives, anesthetics, anxiolytics, and anti-

convulsants

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 Barbiturates

• Large doses result in death b/c of respiratory & CVS

depression

• No longer or rarely used as sedative hypnotics;

– Due to their narrower margin of safety (risk of misuse for

suicide) & their potential to produce physical dependence.

• May be used in anesthesia & treatment of epilepsy.

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 Barbiturates

MoA
 Facilitate the actions of GABA by binding at GABA -A
receptors.
 At high concentrations, barbiturates may also be GABA-
mimetic and inhibit excitatory neurotransmission
 The GABA-A receptor is a ligand gated ion channel membrane
receptor that allows for the flow of Cl through the membrane
in neurons.
barbiturates ↑ duration of GABA mediated Cl- channel opening
Benzodiazepines ↑ frequency of Cl- channel opening
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Barbiturates have been used in the past to treat a
variety of symptoms from insomnia to dementia.

Largely been replaced with drugs such as BZDs due to

their propensity for addiction and reduced effect over
extended use.

Still widely used to treat most seizures including

neonatal seizures.

Used when benzo class drugs fail or in underdeveloped

countries.

Cannot be used for treatment of absence seizures

Enzyme induction (P-450 microsomal enzyme in liver)

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 Characteristics of barbiturate subgroups
Subgroup Drug Lipid Onset DOA Applications
solubility (min) (hr)

Ultra short- Thiopental High 0.5 0.2 Induction of

acting anesthesia,
treatment of
seizures

Short to Secobarbital Moderate 10-15 3 – 4 Treatment of

intermediate- insomnia
acting

Long-acting Phenobarbital Low 60 10-12 Treatment of

seizure

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 Adverse effect of barbiturates
• Drowsiness and decrease motor control
• Induction of P450 enzymes
• Respiratory depression and coma at high dose
• Allergic reactions
• Abrupt cessation-severe withdrawal
symptoms –termer, restlessness, nausea,
seizures, cardiac arrest

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 2. Benzodiazepines
• BZPs are the most widely used anxiolytic drugs
• They are safe and effective
• complete absorbed from the gut hence it can be
given orally
Mechanism of Action:
– The binding of BZDS enhance the affinity of GABA
receptors for GABA, resulting in a more frequent
opening of adjacent chloride channels.
– Enhanced hyper polarization & further inhibition of
neuronal excitations
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 Bzps…
ACTIONS
• Hypnosis, sedation, anxiolysis, anticonvulsant,
• decreased nocturnal acid secretion, skeletal muscle
relaxation.
• Gained popularity over barbiturates because
– BZPs have a high therapeutic index
– Hypnotic doses do not affect respiration & CVS functions
– slight effect on rapid eye movement phase of sleep,
hence there is no hangover
– Produce less physical dependence
– BZPs do not alter the disposition of other drugs by
microsomal enzyme induction
– Presence of BZD antagonist (flumazenil) as antidote 16
• Duration of action of BDZs varies as a
function of the metabolites they produce
– Short acting (eg lorazepam) do not produce
metabolite
t½ (10-20hrs)- can be used for elderly
– Longer acting BZDs (eg. Flurazepam, and
Diazepam) produce active metabolites with
t½ 20-120hrs- avoid in elderly patients

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 BZPs therapeutic use
• Sedative-hypnotic
– Diazepam, flurazepam, temazepam, triazolam
• Anxiety disorders
– Chlorodiazepoxide, clonazepam, lorazepam, oxazepam
• Anticonvulsant
– Diazepam, clonazepam, nitrazepam
• Muscle relaxant
– Diazepam
• Pre-anesthetic medication
– Diazepam
• In peptic ulcer e.g chlorodiazepoxide
• Sedative effects can be reversed with flumazenil
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 BZPs…
Adverse effects
• generally well tolerated, safe In contrast to barbiturates and other
general CNS depressants
• CNS depression  drowsiness, lightheadedness, incoordination
and difficult concentration
• Anterograde amnesia
– Impaired recall of events that take place after dosing
– Especially troublesome with triazolam
• Respiratory depression
– weak respiratory depressants (orally)
– Combination cause significant respiratory depression.
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 BZPs…
Adverse effects
• Abuse
– Have low abuse potential
– Use in pregnancy and lactation
– Are highly lipid soluble and can readily cross the placental
barrier.
– Increased risk of congenital malformation
– Use near term can cause CNS depression in the neonate
– Can enter breast milk with ease and accumulate to toxic
levels in the breast

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 BZPs…
Drug interactions
• Additive effects to other CNS depressants
(including ETOH) and can lead to respiratory
depression, coma, and death.
• Patients should be warned against use of
alcohol and other CNS depressants
Tolerance and physical dependence
• little or no tolerance with anxiolytic and
hypnotic effects
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Other drugs that induce sedation
 Antihistaminics (promethazine, diphenhydramaine)
 Neuroleptics / antidepressant(chlorpromazine,amitryline)
 Opoids (morphine, pethidine)
They have significant sedation effect but not reliable for
treatment of insominia
 β-adrenoceptor antagonists (e.g. propranolol) to treat some
forms of anxiety (for physical symptoms such as sweating,
tremor and tachycardia)
 block of peripheral sympathetic responses
 actors and musicians to reduce the symptoms of stage fright’
 Propranolol produces insominia as a side effect

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ANTI PARKINSON'S DRUGS

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 Parkinson’s disease (PD)
• PD is disorder of mov’t that occurs mainly in the elderly

• Occurs for a variety of possible reasons

– Exposure to certain toxins (manganese dust, carbon-

disulfide etc)

– Drug induced parkinsonism : reserpine, chlorpromazine,

haloperidol & other antipsychotics that block D2

– Post encephalitic parkinsonism : after viral infection

– Idiopathic parkinsonism : unknown cause

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 The hallmark motor features of
Parkinson’s disease (PD)
 The presence of tremor at rest
 Rigidity
 bradykinesia
 postural instability (instability of
balance)

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 Pathophysiology of PD
• The basal ganglia are responsible for controlling automatic
movements of the body by the action of dopamine (DA)

• Degeneration of basal ganglia in the deeper grey matter of the

brain (substantia nigra) causes PD.

• DA level in the brain’s substantia nigra normally fall with ageing

• The level has to fall to one-fifth of normal values for signs of PD

to emerge

• In PD, there is extensive destruction of dopaminergic neurons of

SN (DA deficiency)

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 Pathophysiology
 Ach works in conjunction with DA system to produce
smooth movement

 loss of DA throws off normal DA/Ach balance, since

the level of Ach remains normal

 Basal ganglia are thus prevented from modifying

nerve pathways that control muscle contraction.

 As a result, muscles are overly tense, causing

tremor, joint rigidity, and slow movement

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 Strategy of Treatment
• Symptoms of Parkinson's reflect

– imbalance b/n the excitatory cholinergic neuron & the

greatly diminished number of inhibitory dopaminergic
neurons.

• Therapy is aimed

– to restore the dopamine in the basal ganglia & antagonizing

the excitatory effects of cholinergic neurons.

– Thus re-establishing the correct dopamine and -Ach

balance.

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 Classification of drugs

1. Drugs affecting brain dopaminergic system

a. Dopamine precursors: levodopa

b. Peripheral decarboxylase inhibitors: carbidopa & benserazide

c. Dopaminergic agonists: bromocriptine, lisuride, pergolide,

ropinirole, cabergoline & pramipexole

d. MAO-B inhibitors : Selegiline

e. COMT inhibitors: Entacapone,tolcapone

f. Dopamine facilitator : Amantidine

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 Periphery Brain

3-OMD 3-OMD

COMT COMT Tolcapone

Tolcapone (-)
(-)

Blood brain barrier

Entacapone

Levodopa Levodopa
Carbidopa
DDC DDC
Benserazid (-)

Dopamine
Dopamine
Tolcapone MAO-B
(-) COMT (-)
OMD,O-methyldopa
DDC, dopadecarboxylase 3-MT DOPAC
HVA,homovanilic acid Selegiline
MAO-B
MT,methoxytyramine COMT
(-)
DOPAC,dihydroxy phenylacetic acid
HVA
COMT, catechol-o-methyl transferase
MAO-B, Monoamine oxidase B 31
2. Drugs affecting brain cholinergic system

a. Anticholinergcs: Benzatropine, Trihexyphenidyl

(benzhexol)

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 Levodopa (L-DOPA)
• first-line treatment for PD

• is the immediate metabolic precursor of dopamine

– Prodrug for DA

– Levodopa can cross BBB while DA does not

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 Common Motor Complications
Effect Possible Treatments
End-of-dose “wearing Increase frequency of carbidopa/L-dopa doses; add either
off” (motor COMT inhibitor or MAO-B inhibitor or dopamine agonist
fluctuation)

“Delayed on” or “no Give carbidopa/L-dopa on empty stomach; avoid

on” response carbidopa/L-dopa CR; use apomorphine subcutaneous

Start hesitation Increase carbidopa/L-dopa dose; add a dopamine agonist or

(“freezing”) MAO-B inhibitor; utilize physical therapy along with assistive
walking devices or sensory cues (e.g., rhythmic commands,
stepping over objects)

Peak-dose dyskinesia Provide smaller doses of carbidopa/L-dopa; add amantadine

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 Other adverse effects
• Nausea & anorexia
– Occurs at initial therapy & tolerance gradually
develops (dose can be progressively increased )
– Antiemetics : domperidone (DA antagonist on CTZ )
• Postural hypotension, cardiac arrthymias &
excerbation of angina
– Due to β adrenergic action of peripherally formed DA
– More sever for patients with pre existing heart diseases
• Psychological effects: schizophrenia-like syndrome
– C/I to psychotic patients
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 Dopamine receptor agonists
Act directly on postsynaptic DA receptor types
(primarily D2)
Effective as monotherapy or as adjuncts to carbidopa
/levodopa therapy

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DA receptor agonists available for treatment of PD
 Bromocriptine (Ergot derivative)
– Potent D2 agonist & partial D1 agonist
– High dose is needed if used alone
– Used only in late case as supplement to levodopa
– Also used for treatment of hyperprolactinemia (reduce
prolactine release) in lower doses than for PD

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 DA receptor agonists

 Pergolide
 Ergot derivative
 Agonist of both classes (D1 & D2)
 More effective than bromocriptine in relieving the
symptoms & signs of PD
 Increase "on-time" among response fluctuators
 Allow the levodopa dose to be reduced

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 DA receptor agonists

 Pramipexole
– Nonergoline derivative
– Selective activity at D2 class (D2 & D3 receptors)
• little or no activity at D1
– Effective when used as monotherapy for mild
parkinsonism
– Also helpful in patients with advanced disease
• permitting dose of levodopa to be reduced &
smoothing out response fluctuations
– Scavenge hydrogen peroxide /neuroprotective effect/

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 DA receptor agonists

 Ropinirole
– Nonergoline derivative
– Relatively pure D2 receptor agonist
– Effective as monotherapy in patients with mild PD
– Used as a means to smoothen the response to
levodopa in patients with more advanced disease &
response fluctuations
– Metabolized by CYP1A2
• drugs metabolized by CYP1A2 may significantly
reduce clearance of ropinirole
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 DA receptor agonists

• Initial treatment with bromocriptine or pergolide (non

selective agonists)
– may cause hypotension
– induce nausea & fatigue
• Symptoms are transient & require slow upward
adjustment of the dose over a period of weeks to
months
• Selective agonists (pramipexole & ropinirol) are well
tolerated
– Can be initiated more quickly
– Therapeutic doses can be achieved in a week or less
than a week
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Adverse effects of DA agonists
GIT effects
• Anorexia , nausea & vomiting : can be
minimized by taking the medication with meals
• Constipation, dyspepsia, & symptoms of reflux
esophagitis may also occur
CVS effects
• Postural hypotension at the initiation of therapy
• Cardiac arrhythmias an indication for
discontinuing treatment
• Cardiac valvulopathy may occur with pergolide
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 Adverse effects of DA agonists

Dyskinesias
• Abnormal movements similar to those produced by
levodopa
– Can be reversed by reducing the total dose of the drug
Mental disturbances
• Confusion, hallucinations, delusions & other
psychiatric reactions
• More common & severe with DA receptor agonists
than with levodopa
• They clear on withdrawal of the medication
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 DA receptor agonists

C/I
• DA agonists are C/I in patients with
– History of psychotic illness
– Recent myocardial infarction
– Active peptic ulceration
• Patients with peripheral vascular disease should
avoid taking ergot-derived agonists

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MAO-B inhibitors
MAO-B : The predominant form of MAO in the striatum &
responsible for most of oxidative metabolism of DA in the
brain
Selegiline (deprenyl)
• At low to moderate doses ( < 10mg/day), it is selective &
irreversible MAO-B inhibitor
– It does not metabolize peripheral catecholamine
– At dose > 10mg/day , MAO-A can be inhibited
• Used as adjunctive therapy for patients with declining or
fluctuating response to levodopa

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 MAO-B Inhibitor

Selegiline
• In advanced PD, it may aggravate the adverse
motor & cognitive effects of levodopa therapy
• Rasagiline (MAO–B inhibitor )
– More potent than selegiline in preventing MPTP
induced PD

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COMT inhibitors
– Tolcapone & Entacapone

• Addition of COMT inhibitors to carbidopa / levodopa

combination delays ’’wear off’’ phenomenon

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 COMT Inhibitors

Tolcapone
• Has long duration of action
• Inhibit both central & peripheral COMT
• Associated with hepatotoxicity
– Should be used with appropriate monitoring for
hepatic injury only when other therapies are not
effective
Entacapone
• Has short duration of action
• Act peripherally

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Amantadine
• Antiviral agent with several pharmacological
effects
• MoA for its anti PD activity is not clear, possibly
by
– Facilitating synthesis, release or reuptake of DA in
the striatum
– Its anticholinergic properties
– Blocking NMDA glutamate receptors

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Muscarinic receptor antagonists
• Drugs with higher central to peripheral
anticholinergic ratio than atropine but they have
similar pharmacological profile
• Reduce the unbalanced cholinergic activity in
striatum
• The only drugs effective in drug (phenothiazine)
induced parkinsonism
• Treatment has to start from small dose & gradually
increased until benefit occurs or side effects limit
further increment

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 Muscarinic receptor antagonists

• Benzatropine (muscarinic receptor antagonist) used

for parkinsonism caused by antipsychotic drugs
• Other antimuscarnic agents: Biperiden,
orphenadrine, procyclidine, trihexyphenidyl
• Side effect profile is similar to atropine
– Dryness of mouth, nausea, constipation, palpitation,
cardiac arthymias, confusion, agitation, restlessness,
mydriasis, increased intraocular pressure, defective
accommodation

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