CNS part 1

Sedative, hypnotics &
anxiolytic drugs
Dr. Karun Kumar
Senior Lecturer
Dept. of Pharmacology

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
• Slowly acting drugs with flatter dose-response
curves

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
• Quicker onset, shorter duration and steeper dose-
response curves
• A hypnotic at lower dose may act as sedative
• Most important use  Insomnia

Uses of barbiturates
1. Phenobarbitone in epilepsy
2. Thiopentone in anaesthesia

Adverse effects
1. Side effects  Hangover, mental confusion,
impaired performance and traffic accidents
2. Idiosyncrasy  In an occasional patient
barbiturates produce excitement
3. Hypersensitivity  Rashes, swelling of eyelids,
lips, etc.
4. Tolerance and dependence  Tolerance develops
on repeated use. Barbiturates have considerable
abuse liability

Interactions
1. Barbiturates induce the metabolism of Warfarin,
steroids (including contraceptives), Tolbutamide,
Griseofulvin, Chloramphenicol, Theophylline.
2. Additive action with other CNS depressants
(Alcohol, antihistamines, opioids, etc.)
3. Sodium valproate increases plasma concentration
of Phenobarbitone
4. Phenobarbitone competitively inhibits as well as
induces Phenytoin and Imipramine metabolism:
complex interaction
5. Phenobarbitone decreases absorption of
Griseofulvin from the g.i.t.

Why Benzodiazepines ?
1. They have a high therapeutic index
2. Hypnotic doses do not affect respiration or
cardiovascular functions
3. BZDs have practically no action on other body
systems. Only on i.v. injection the BP falls and
cardiac contractility decreases
4. BZDs cause less distortion of sleep architecture
5. BZDs do not alter disposition of other drugs by
microsomal enzyme induction

6. They have lower abuse liability: tolerance is mild,
psychological and physical dependence, drug seeking
and withdrawal syndrome are less marked
7. A specific BZD antagonist flumazenil is available
which can be used in case of poisoning

Site 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
• Ataxia is due to action on cerebellum

Mechanism of action
• BZDs act by enhancing presynaptic/postsynaptic
inhibition through a specific BZD receptor which is
an integral part of the GABAA receptor–Cl¯ channel
complex
• The binding site for GABA is located on the β
subunit, while the α/γ subunit interface carries the
BZD binding site
• The modulatory BZD receptor increases the
frequency of Cl¯ channel opening induced by
submaximal concentrations of GABA

• BZDs also enhance GABA binding to GABAA
receptor
• The GABAA antagonist Bicuculline antagonizes BZD
action in a noncompetitive manner
• BZDs do not themselves increase Cl¯ conductance;
have only GABA facilitatory but no GABA mimetic
action

Adverse effects
• Side effects of hypnotic doses  Dizziness, vertigo,
ataxia, disorientation, amnesia, prolongation of
reaction time—impairment of psychomotor skills
(should not drive)
• Hangover is less common
• Weakness, blurring of vision, dry mouth and
urinary incontinence are sometimes complained
• Tolerance to the sedative effects develops
gradually, but there is little tendency to increase
the dose

• Cross tolerance to alcohol and other CNS
depressants occurs
• The dependence producing liability of BZDs is low
• They are weak reinforcers (less pleasurable) and
seldom abused alone
• Withdrawal syndrome is generally mild
• Drug seeking behavior is not prominent

Interactions
1. BZDs synergise with alcohol and other CNS
depressants leading to excessive impairment
2. Concurrent use with sod. valproate has provoked
psychotic symptoms
3. Drug interactions due to microsomal enzyme
induction are not significant
4. Their action can be prolonged by CYP3A4
inhibitors like Ketoconazole, Erythromycin and
others
5. Cimetidine, Isoniazid and Oral contraceptives also
retard BZD metabolism

Non-benzodiazepine hypnotics
• Produce hypnotic amnesic action with only weak
antianxiety, muscle relaxant and anticonvulsant
effects
• They have lower abuse potential than hypnotic
BZDs
• Given their shorter duration of action, they are
being preferred over BZDs for the treatment of
insomnia

Uses
1. As hypnotic  When indicated, BZDs or the
newer non-BZDs like Zolpidem, Zaleplon are the
hypnotic of choice
• Dentists are likely to need to prescribe a hypnotic
either to ensure sleep night before the dental
procedure in an apprehensive patient, or to
supplement analgesics before and after dental
surgery
• A longer acting BZD, like Diazepam, is mostly
preferred

Other uses
1. As anxiolytic and for day-time sedation
2. As anticonvulsant, especially emergency control
of status epilepticus, febrile convulsions, tetanus,
etc.
3. As centrally acting muscle relaxant for muscular
spasms

4. For preanaesthetic medication, i.v. anaesthesia
and conscious sedation
5. Alcohol withdrawal in dependent subjects
6. Along with analgesics, NSAIDs, spasmolytics,
antiulcer and as adjuvants to treat ‘gas’ or
nonspecific dyspeptic symptoms

Ethyl Alcohol (Pharmacological
actions)
1. Local actions  Mild rubefacient and
counterirritant when rubbed on the skin. By
evaporation it produces cooling. Alcohol is an
astringent—precipitates surface proteins and
hardens the skin. By precipitating bacterial
proteins it acts as an antiseptic
2. CNS  Alcohol is a neuronal depressant.
Hesitation, caution, self-criticism and restraint
are lost first. Mood and feelings are altered;
anxiety may be allayed

• ‘Hangover’ (headache, dry mouth, laziness,
disturbed mood, impaired performance) may occur
the next morning
• Chronic alcohol abuse damages brain neurones,
causes shrinkage of brain
• Any measurable concentration of alcohol produces
a measurable slowing of reflexes: driving is
dangerous

Other actions
1. Vasodilatation, flushing, tachycardia
2. Resp. centre depressed (at high conc.)
3. Heat loss is greater in cold
4. GERD is worsened
5. Cirrhosis of liver (chronic alcoholism)
6. Small to moderate alcohol ↓ CAD risk
7. Urine flow may ↑ (ADH inhibition)
8. Impairment of sexual performance
9. Hyperglycaemia followed by hypoglycaemia

Contraindications
1. Peptic ulcer, hyperacidity and gastroesophageal
reflux patients (alcohol increases gastric secretion
and relaxes LES)
2. Epileptics: seizures may be precipitated
3. Severe liver disease patients
4. Unstable personalities: they are likely to abuse it
and become excessive drinkers
5. Pregnant women  “Foetal alcohol syndrome”
(Intrauterine and postnatal growth retardation,
↓ IQ, microcephaly, cranio-facial and other
abnormalities, and immunological impairment→
↑ susceptibility to infections)

Toxicity
1. Moderate drinking  Nausea, vomiting, flushing,
hangover, traffic accidents
2. Acute alcoholic intoxication  Hypotension,
gastritis, hypoglycemia, respiratory depression,
collapse, coma and death
3. Chronic alcoholism  Physical dependence
occurs only on heavy and round-the-clock
drinking (if alcohol is present in the body
continuously). Psychic dependence often occurs
even with moderate drinking

Dental implications
1. Alcoholics have higher incidence of heavy dental
plaque, calculus deposits, chronic periodontitis,
and tooth loss due to poor oral hygiene
2. Dentists while prescribing Metronidazole or
certain Cephalosporins for periodontal infections
should warn patients not to drink
3. Concurrent use of NSAIDs and alcohol should be
prohibited

Clinical uses
1. As antiseptic and disinfectant
2. Rubefacient & counterirritant for sprains, joint
pains, etc.
3. Rubbed into the skin to prevent bedsores
4. Astringent action of alcohol is utilized in
antiperspirant and aftershave lotions
5. Low concentrations as appetite stimulant &
carminative
6. To treat methanol poisoning

Interactions
1. Alcohol synergises with anxiolytics,
antidepressants, antihistaminics, hypnotics,
opioids → marked CNS depression with motor
impairment can occur: Chances of accidents
increase
2. Individuals taking a sulfonylurea, cefoperazone,
or metronidazole have experienced bizarre,
somewhat disulfiram-like reactions when they
consume alcohol

3. Acute alcohol ingestion inhibits, while chronic
intake induces metabolism of Tolbutamide,
Phenytoin and some other drugs
4. Hypoglycaemic action of insulin and sulfonylureas
is enhanced by alcohol ingestion
5. Aspirin and other NSAIDs cause more gastric
bleeding when taken with alcohol
6. Formation of toxic metabolite of Paracetamol
(NAPQI) is increased in chronic alcoholics

Antiepileptic drugs
• Seizure  Paroxysmal abnormal discharge at high
frequency, from an aggregate of neurons in
cerebral cortex
• Epilepsy  Condition characterized by recurrent
episodes of such seizures
• Convulsions  Involuntary, violent and spasmodic
or prolonged contractions of skeletal muscle

Classification of seizures
1. Generalized (Both cerebral hemispheres involved)
1. Generalised tonic-clonic seizures
2. Absence seizures
3. Atonic seizures
4. Myoclonic seizures
5. Infantile spasms (Hypsarrhythmia)
2. Partial (Restricted to a discrete area belonging to
1 cerebral hemisphere only)
1. Simple partial seizures
2. Complex partial seizures
3. Simple partial or complex partial seizures secondarily
generalized

Generalized seizures
1. Generalised tonic-clonic seizures (GTCS, major
epilepsy, grand mal)  Commonest, lasts 1–2
mins. 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) 
Prevalent in children, 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
5.Infantile spasms (Hypsarrhythmia)  Seen in
infants. Intermittent muscle spasm and progressive
mental deterioration

Partial seizures
1. Simple partial seizures (SPS, cortical focal
epilepsy)  lasts 1/2–1 min; 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
2. Complex partial seizures (CPS, temporal lobe
epilepsy, psychomotor)  Attacks of bizarre and
confused behaviour and purposeless movements,
emotional changes lasting 1–2 min along with
impairment of consciousness

3. Simple partial or complex partial seizures
secondarily generalized  The partial seizure occurs
first and evolves into generalized tonic-clonic
seizures with loss of consciousness

Phenobarbitone
• Enhancement of GABAA receptor mediated synaptic
inhibition appears to be most important
mechanism
• Phenobarbitone has specific anticonvulsant activity
• The higher anticonvulsant: hypnotic ratio of
phenobarbitone may be due to its minimal effect
on Ca2+ channels and glutamate release compared
to hypnotic barbiturates

• With continued use of Phenobarbitone sedation
wanes off but not anticonvulsant action
• The major drawback of Phenobarbitone as an
antiepileptic is its sedative action
• Long term administration (as needed in epilepsy)
may produce additional side effects like—
behavioral abnormalities, diminution of
intelligence, impairment of learning and memory,
hyperactivity in children, mental confusion in older
people

Phenytoin (Adverse effects)
• Plasma level monitoring needed (0 order k.)
• Hypertrophy of gums
• Enzyme induction
• Neutropenia and other hypersensitivity reactions
• Young girls beware ! Causes hirsutism, coarsening
of facial features and acne
• Teratogenic
• Osteomalacia

• Interference with folate absorption leads to
megaloblastic anemia
• Neurological manifestations at higher doses 
Ataxia, vertigo, nystagmus, diplopia

Uses
• Less commonly used now because side effects are
frequent and marginal overdose causes steep rise
in plasma concentration, producing neurotoxicity.
1. Generalized tonic-clonic, simple and complex
partial seizures. It is ineffective in absence seizure
2. Trigeminal neuralgia  second choice drug to
carbamazepine

Interactions
1. Phenobarbitone competitively inhibits phenytoin
metabolism, while by enzyme induction both
enhance each other’s degradation—
unpredictable overall interaction
2. Carbamazepine and phenytoin induce each
other’s metabolism
3. Valproate displaces protein bound phenytoin and
decreases its metabolism  Plasma level of
unbound phenytoin increases

4. Chloramphenicol, Isoniazid, Cimetidine and
Warfarin inhibit phenytoin metabolism  Can
precipitate its toxicity
5. Phenytoin induces microsomal enzymes and
increases degradation of steroids (failure of oral
contraceptives), Doxycycline, Theophylline

Fosphenytoin
• Water soluble prodrug of Phenytoin has been
introduced to overcome the difficulties in i.v.
administration of Phenytoin, which it has replaced
for use in status epilepticus.
• On i.v. injection it is less damaging to the intima
• While Phenytoin cannot be injected in a drip of
glucose solution (because it gets precipitated),
fosphenytoin can be injected with both saline and
glucose

Carbamazepine
• First line antiepileptic drug for focal seizures and
trigeminal neuralgia
• Manic depressive illness and acute mania  As an
alternative to Lithium
• Carbamazepine produces dose-related
neurotoxicity  sedation, dizziness, vertigo,
diplopia and ataxia. Vomiting, diarrhoea, worsening
of seizures are also seen with higher doses
• Hypersensitivity reactions are rashes,
photosensitivity, hepatitis, lupus like syndrome and
rarely agranulocytosis, aplastic anemia

Lupus like syndrome
• Autoimmune disorder caused by a reaction to
certain medications
• Symptoms are muscle and joint pain sometimes
with swelling;flu-like symptoms of fatigue and fever
• SHIP drugs are responsible
1. Sulfonamides incl. dapsone and PAS
2. Hydralazine
3. Isoniazid
4. Procainamide

Interactions
• Carbamazepine is an enzyme inducer; can reduce
efficacy of Haloperidol, oral contraceptives
• Metabolism of Carbamazepine is induced by
Phenobarbitone, Phenytoin, Valproate and vice
versa
• Erythromycin, Fluoxetine, Isoniazid inhibit
metabolism of carbamazepine

Oxcarbazepine
• Newer congener of carbamazepine
• Toxic effects due to the epoxide metabolite are
avoided
• Drug interactions and auto induction of own
metabolism are less marked, because it is a weak
enzyme inducer
• Risk of hepatotoxicity is estimated to be lower than
carbamazepine; but that of hyponatremia is more
• Indications are the same as for carbamazepine, but
it may be better tolerated
• Dose to dose it is 1½ times less potent

Valproic acid (Sodium valproate)
• Valproate appears to act by multiple mechanisms:
1. A phenytoin-like frequency-dependent
prolongation of Na+ channel inactivation.
2. Weak attenuation of Ca2+ mediated ‘T’ current
(Ethosuximide like)
3. Augmentation of release of inhibitory transmitter
GABA by inhibiting its degradation (by GABA-
transaminase)
4. Blockade of excitatory NMDA type of glutamate
receptor

Uses
• Drug of choice for
1. Generalised tonic clonic seizures
2. Absence seizures
3. Myoclonic seizures
4. Atonic seizures
• Alternative/adjuvant drug for SPS and CPS.
• Mania and bipolar illness  As alternative to
Lithium

Adverse effects
• Vomiting
• Alopecia
• Liver toxicity
• Pancreatitis
• Rash
• Obesity
• Agranulocytosis
• Teratogenic (Neural tube defects in offspring)

• E (dEntist)  Dentist may face excess bleeding
while executing a dental procedure as Valproate
causes increased bleeding tendency
• E  Epigastric pain

Interactions
1. Valproate increases plasma levels of Phenobarbitone
and lamotrigine by inhibiting their metabolism
2. It displaces Phenytoin from protein binding site and
decreases its metabolism → Phenytoin toxicity
3. Valproate inhibits hydrolysis of active epoxide
metabolite of Carbamazepine
4. Concurrent administration of Clonazepam and
valproate is contraindicated because absence status
may be precipitated
5. Foetal abnormalities are more common if Valproate
and Carbamazepine are given concurrently

Divalproex (Semisodium
valproate)
• Coordination compound of valproic acid with
sodium valproate (1:1)
• Oral absorption is slower, but bioavailability is the
same
• Gastric tolerance may be better
• Indications are similar to Valproate

Clonazepam
• BZD with prominent anticonvulsant properties
(potentiates GABA induced Cl- influx)
• At large doses, high frequency discharges are
inhibited akin to Phenytoin
• Pharmacokinetics  Oral abs. is good. 85% bound
to plasma proteins, completely metabolized in liver
and excreted in urine; t½ averages 24 hours
• A/E  Sedation and dullness. Motor disturbances
and ataxia are dose-related adverse effects
• Uses  Absence seizures. Also useful adjuvant in
myoclonic and akinetic epilepsy

Clobazam
• Less sedative and longer acting than Diazepam
• Anxiolytic & is useful in partial, secondarily
generalized tonic-clonic as well as absence and
atonic seizures, including some refractory cases
• Sedation and psychomotor retardation are less
prominent, but side effect profile is similar to other
BZDs
• MOA  Acts by facilitating GABA action
• Use  Adjuvant to other antiepileptic drugs like
phenyt., CBMZ or valproate in refractory epilepsy

Lamotrigine
• Blocks voltage sensitive Na+ & N-type Ca2+ channels
• Broad-spectrum antiepileptic
• Add-on/monotherapy in refractory cases of partial
seizures and GTCS
• Absence and myoclonic or akinetic epilepsy cases
have also been successfully treated
• S/E  Sleepiness, dizziness, diplopia, ataxia and
vomiting. Rash may be a severe reaction,
particularly in children, requiring withdrawal

Gabapentin
• Enhances GABA release, but does not act as agonist
at GABAA receptor
• Added to a 1st line drug, ↓ seizure frequency in
refractory partial seizures with or without general.
• Gabapentin and its newer congener Pregabalin exert
a specific analgesic effect in neuropathic pain
• 1st line drug for pain due to diabetic neuropathy,
postherpetic & other neuralgias
• Some prophylactic effect in migraine
• S/E  Sedation, tiredness, dizziness & unsteadiness

Topiramate
• Broad spectrum anticonvulsant drug acting by :-
1. Prolongation of Na+ channel inactivation
2. Activation of GABAA receptor
3. Inhibition of AMPA receptors for Glutamate
• Monotherapy or supplementing primary
antiepileptic drug in refractory SPS, CPS, GTCS,
myoclonic epilepsy
• A/E  Impairment of attention, sedation, ataxia,
word finding difficulties, poor memory, weight loss,
paresthesias and renal stones.

Treatment of epilepsies
• Antiepileptic drugs suppress seizures, but do not
cure the disorder
• The aim of drugs is to control and totally prevent all
seizure activity at an acceptable level of side effects
• The cause of epilepsy should be searched in the
patient; if found and treatable, an attempt to
remove it should be made
• Some general principles of symptomatic treatment
with antiepileptic drugs are 

1. Choice of drug and dose is according to the
seizure type(s) and need of the individual patient
2. Initiate treatment early, because each seizure
episode increases the propensity to further
attacks. Start with a single drug, preferably at low
dose, gradually increase dose till full control of
seizures or side effects appear. If full control is
not obtained at maximum tolerated dose of one
drug, substitute another drug. Use combinations
when all reasonable monotherapy fails.

3. A single tonic-clonic seizure in a subject with no
predisposing factor for development of epilepsy
(history of head injury, family history of epilepsy,
neurological abnormality, abnormal EEG or brain
scan) may not merit initiation of antiepileptic therapy
4. Therapy should be as simple as possible. A seizure
diary should be maintained.
5. All drug withdrawals should be gradual (except in
case of toxicity). Prolonged therapy (may be life-long,
or at least 3 years after the last seizure) is needed.
Stoppage of therapy may be attempted in selected
cases.

6. Dose regulation may be facilitated by monitoring
of steady state plasma drug levels
7. When women on antiepileptic therapy conceive,
antiepileptic drugs should not be stopped.
Lamotrigine has widest spectrum (GTCS, typical
Absence, atypical absence, myoclonic, atonic, focal
seizures) and is preferred drug in pregnancy.
Prophylactic folic acid supplementation in 2nd and
3rd trimester along with vit. K in the last month of
pregnancy is recommended, particularly in women
receiving antiepileptic drugs to minimize neural tube
defects and bleeding disorder respectively in the
neonate

Dental implications
1. Dentists have to recognize and manage Phenytoin
induced gum hypertrophy
2. In an epileptic patient, dental procedure should
be carried out only after ensuring that the patient
is under adequate anticonvulsant drug cover and
has taken his/her medication
3. In the event of a patient developing an attack of
GTCS during dental procedure, the first priority is
to prevent injuries due to biting or fall. Ensure
that the patient is secure on the flat dental chair
or floor

• Any denture or instrument should be immediately
removed from the mouth
• The head should be turned to the side to prevent
the tongue from falling back and obstructing the
airway
• Give oxygen through a face mask to support
respiration if any sign of cyanosis is seen
• Do not attempt to stop convulsive movements by
restraining the patient
• In case the seizures do not stop or recur within 10-
20 minutes, management is as for status epilepticus

Status epilepticus
• When seizure activity occurs for >30 min, or 2 or
more seizures occur without recovery of
consciousness  Status epilepticus
• Recurrent tonic-clonic convulsions without
recovery of consciousness in between is an
emergency; fits have to be controlled as quickly as
possible to prevent death and permanent brain
damage

Management of status epilepticus
1. Maintain patent airway
2. Dextrose [20-50 ml of 50% soln.] injected i.v. (If
seizure is due to hypoglycemia)
3. Lorazepam 4 mg injected i.v. over 2 mins.,
repeated once after 10 min if required, is the first
choice drug now
4. Diazepam 10 mg injected i.v. at 2 mg/min
5. Fosphenytoin 100–150 mg/min i.v. infusion to a
maximum of 1000 mg (15–20 mg/kg) under
continuous ECG monitoring is a slower acting
drug which should be given if the seizures recur
or fail to respond 20 min after onset, despite
Lorazepam / Diazepam

4. Phenytoin sodium should be used only when
fosphenytoin is not available
5. Phenobarbitone sodium 50–100 mg/min i.v.
injection to a maximum of 10 mg/kg is another
slower acting drug which can be used as alternative
to fosphenytoin
6. Refractory cases may be treated with i.v.
Midazolam/ Propofol/ Thiopentone anaesthesia,
with or without curarization
7. General measures, including maintenance of
airway (intubation if required), oxygenation, fluid
and electrolyte balance, BP, normal cardiac
rhythm, euglycaemia and care of the unconscious
must be taken

Parkinsonism
• P  Pill rolling tremors
• A  Akathisia (inability to sit still)
• R  Rigidity
• K  Kinesias (akinesia, bradykinesia)
• I  Instable (stooped) posture
• N  No arm swinging in rhythm with legs
• S  Sialorrhoea (drooling or excessive salivation)
• O  Oculogyric crisis (Eyes are held fixed for a
variable length of time)

• N  Nervous depression
• I  Involuntary tremors
• S  Seborrhoea
• M  Masked facial expression
• Parkinsonism applies for a disease state having the
above features whereas Parkinson’s Disease is
restricted to primary or idiopathic Parkinsonism

Antiparkinsonian Drugs
• Levodopa  Levodopa has a specific salutary effect
in PD
• More than 95% of an oral dose is decarboxylated in
the peripheral tissues (mainly gut and liver).
• DA thus formed is further metabolized, and the
remaining acts on heart, blood vessels, other
peripheral organs and on CTZ
• About 1–2% of administered levodopa crosses to
the brain, is taken up by the surviving dopaminergic
neurones, converted to DA which is stored and
released as a transmitter.

Actions
1. CNS  Levodopa hardly produces any effect in
normal individuals. Marked symptomatic
improvement occurs in parkinsonian patients.
Hypokinesia and rigidity resolve first, later tremor
as well. Secondary symptoms of posture, gait,
handwriting, speech, facial expression, mood, self
care and interest in life are gradually normalized.
2. CVS  The peripherally formed DA can cause
tachycardia by acting on β adrenergic receptors.
Postural hypotension is quite common.

3. CTZ  The DA formed peripherally gains access to
the CTZ without hindrance—elicits nausea and
vomiting by stimulating D2 receptors
4. Endocrine  DA acts on pituitary mammotropes
to inhibit prolactin release

Adverse Effects
1. Nausea and vomiting
2. Postural hypotension  Care should be taken by
the dentist that patients on levodopa therapy do
not sit up and leave the dental chair abruptly
from a reclining position
3. Cardiac arrhythmias
4. Exacerbation of angina
5. Alteration in taste sensation
6. Abnormal movements  Orofacial dyskinesia

7. Behavioural effects  Range from mild anxiety,
nightmares, etc. to severe depression, mania,
hallucinations, mental confusion or frank psychosis.
• Levodopa is contraindicated in patients with
psychotic illness.
8. Fluctuation in motor performance  After 2–5
years of therapy, the level of control of parkinsonian
symptomatology starts showing fluctuation. ‘End of
dose’ deterioration develops into rapid ‘switches’ or
‘on-off’ effect. With time ‘all or none’ response
develops, i.e. the patient is alternately well and
disabled.

Interactions
1. Pyridoxine  Abolishes the therapeutic effect of
levodopa by enhancing its peripheral
decarboxylation
2. Phenothiazines, Butyrophenones,
Metoclopramide reverse the therapeutic effect of
levodopa by blocking DA receptors
3. Antihypertensive drugs  Postural hypotension
caused by levodopa is accentuated

Peripheral decarboxylase
inhibitors
• Carbidopa and benserazide are extracerebral dopa
decarboxylase inhibitors; they do not penetrate
blood-brain barrier and do not inhibit conversion of
levodopa to DA in the brain.
• Administered along with levodopa, they increase its
t½ in the periphery and make more of it available
to cross blood-brain barrier and reach its site of
action

Benefits of the combination
1. The plasma t½ of levodopa is prolonged and its
dose is reduced to approximately 1/4th.
2. Systemic concentration of DA is reduced, nausea
and vomiting are not prominent
3. Cardiac complications are minimized.
4. Pyridoxine reversal of levodopa effect does not
occur.
5. ‘On-off’ effect is minimized
6. Degree of improvement may be higher

Problems not resolved
1. Involuntary movements
2. Behavioral abnormalities
3. Excessive day time sleepiness in some patients
4. Postural hypotension

Dopaminergic agonists
• The DA agonists can act on striatal DA receptors
even in advanced patients who have largely lost the
capacity to synthesize, store and release DA from
levodopa
• Longer acting, can exert subtype selective
activation of DA receptors involved in parkinsonism
and not share the concern expressed about
levodopa of contributing to dopaminergic neuronal
damage by oxidative metabolism

Ropinirole and Pramipexole
• First choice drugs for Parkinsonism (preferred over
levodopa); selective D2/D3 receptor agonists with
negligible affinity for D1 and nondopaminergic
receptors
• The therapeutic effect as supplementary drugs to
levodopa in advanced cases of PD as well as side
effect profile is similar to bromocriptine, but they
are better tolerated with fewer GI symptoms
• Side-effects are nausea, dizziness, hallucinations,
and postural hypotension and episodes of day time
sleep

Side effects of
Dopaminergic
agonists

Selegiline
• It is a selective and irreversible MAO-B inhibitor
• MAO-A and MAO-B  Present in peripheral
adrenergic structures and intestinal mucosa
• MAO-B  Brain and blood platelets
• Unlike nonselective MAO inhibitors, Selegiline in
low doses (10 mg/day) does not interfere with
peripheral metabolism of dietary amines;
Accumulation of CAs and hypertensive reaction
does not develop

Adverse Effects
• Postural hypotension
• Nausea
• Confusion
• Accentuation of levodopa induced involuntary
movements and psychosis

Interactions
• Selegiline interacts with pethidine possibly by
favouring its metabolism to norpethidine which
causes excitement, rigidity, hyperthermia,
respiratory depression.
• It may also interact with tricyclic antidepressants
and selective serotonin reuptake inhibitors

Central anticholinergics
• Act by reducing the unbalanced cholinergic activity
in the striatum of Parkinsonian patients
• Only drugs effective in drug (phenothiazine)
induced parkinsonism
• Sialorrhoea is controlled by their peripheral action
• Trihexyphenidyl is the most commonly used drug
• Xerostomia caused by them may aggravate dental
caries

CNS part 1

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CNS part 1

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