Vertigo 2008

Vertigo
A slide kit

Picture adapted from Borg E, Counter A. Pour la Science 1989;144:65. © Pour la science
GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved

What is vertigo?
Vertigo is:
• A type of dizziness
• A sensation of movement typically characterised by
feelings of rotation or spinning

Baloh RW. Lancet 1998;352:1841–6. Mukherjee A et al. JAPI 2003;51:1095–101.
Sloane PD et al. Ann Intern Med 2001;134:823–32.

2

Vertigo can be objective or subjective
Objective vertigo:
• the patient perceives that the environment is
moving around him/her
Subjective vertigo:
• the patient feels himself/herself moving in a static
environment

Mukherjee A et al. JAPI 2003;51:1095–101. Salvinelli F et al. Clin Ter 2003;154:341–8.

3

Vertigo is one of four types of dizziness
Dizziness

Other
Vertigo Presyncope Disequilibrium
subtypes
• An illusion of • A feeling of • A sense of • Swimming or
movement, faintness or unsteadiness in the floating
usually loss of lower body sensations
rotation consciousness • No effect on feelings • Feelings of
in head dissociation
• Relieved when • Difficult to
sitting down describe

Drachman DA, Hart CW. Neurology 1972;22:323–4. Sloane PD et al. Ann Intern Med 2001;134:823–32.

4

Etiology of vertigo
Vertigo related to inner ear
• Benign paroxysmal positional vertigo (BPPV)
• Meniere’s disease
• Labyrinthitis
• Trauma (labyrinthine concussion)
• Aminoglycoside toxicity
Vertigo related to the vestibular nerve
• Vestibular neuritis
• Nerve compression due to meningioma or schwannoma
Vertigo related to brain stem
• Physiological (visual-vestibular mismatch)
• Demyelination (multiple sclerosis)
• Migraine
• Vertebrobasilar insufficiency (as in stroke or TIA)
• Drug toxicities (with anticonvulsants, aspirin, alcohol)
Allen CMC, Lueck CJ. Neurological disease. In: Christopher H, Edwin RC, Nicholas AB, eds. Davidson’s Principles and
Practice of Medicine. 19th ed. Edinburgh: Churchill Livingstone;2002:1103-12310.

5

Vertigo: Pathophysiological Pathways
Endolymph movement, depending on the direction of flow
and deflection of otoliths by gravity, either stimulates or
inhibits neuronal output from the attached hair cells
Nerve impulses from the vestibular system are transmitted
to the vestibular nuclei in the brain stem and cerebellum
through the eighth cranial nerve
From there, connections are made to the oculomotor
system, spinal cord, and cerebral cortex, which integrate
the information to produce the perception of motion
Vertigo results from lesions or disturbances along this
pathway
Robert BD, Mark DC. Syncope, Faintness, Dizziness, And vertigo. In: Dennis LK, Eugene B, Anthony SF et al, eds.
Harrison’s Principles of Internal Medicine.16th ed. New York:McGraw-Hill;2005:126-133.

6

Vertigo: Role of Neurotransmitters
Neurotransmitters that work centrally and
peripherally include:
• Acetylcholine: Functions as an excitatory
neurotransmitter in central and peripheral pathways
• Glutamate: Maintains the resting discharge of the
central vestibular neurons; may modulate synaptic
transmission in the VOR arc
• GABA: Thought to be inhibitory for commissures of
the medial vestibular nucleus
McLean MJ. Principles of neuropharmacology and therapeutics. In: Bradley WG, Daroff RB, Fenichel GM, Marsden CD, eds.
Neurology in Clinical Practice. 3rd ed. Boston: Butterworth Heinemann;2000:867-898.

7

Vertigo: Presentation
Sensation of motion either of the person or the environment
In addition, the following may be present:
• Nausea or vomiting
• Abnormal eye movements
• Sweating
Duration of symptoms can vary from a few minutes to hours
and can be constant or episodic
May also be associated with visual disturbances, weakness,
decreased level of consciousness, difficulty in speaking

Troost BT. Dizziness and vertigo. In: Bradley WG, Daroff RB, Fenichel GM, Marsden CD, eds. Neurology in Clinical Practice.
3rd ed. Boston: Butterworth Heinemann;2000:239-240.

8

Vertigo episodes are debilitating and are more
than just a sensation of movement
Vertigo episodes:
• are characterised by a sensation of movement, usually spinning
or rotating
• vary in intensity and duration
• are usually unpredictable
• are often accompanied by:
 nausea
 vomiting
 imbalance
 anxiety
 sweating
 nystagmus

Baloh RW. Lancet 1998;352:1841–6. Mukherjee A et al. JAPI 2003;51:1095–101.
Salvinelli F, Firrisi L, Casale M, et al. Clin Ter 2003;154:341–8.

9

Vertigo is a continuous burden
Between vertigo episodes there may be:
• Headaches
• Instability
• General malaise
• Anxiety and depression
• Fear over recurrence of episodes
These symptoms may have a negative effect
on quality of life
Fielder H et al. Clin Otolaryngol 1996;21:124–6. Hägnebo C et al. Scand Audiol 1997;26:69–76. Lopez-Escamez JA,
Lopez-Nevot A. Acta Otorrinolaringol Esp 2000;51:377–82. Mendel B et al. Clin Otolaryngol Allied Sci 1999;24:286–93.
Monzani D et al. J Psychosom Res 2001;50:319–23. Salvinelli F et al. Clin Ter 2003;154:341–8.

10

Vertigo can have a negative impact on quality
of life
Women with vertigo Weighted population mean Men with vertigo
Mean score (scale of 0-100) Mean score (scale of 0-100)

QoL parameter (SF-36)
Physical functioning
Limitations due
to emotions
Limitations due p<0.05 p<0.05
to physical problems
p<0.05
Social functioning
Mental health
Bodily pain
Vitality p<0.05
General health
perception
Do we take vertigo seriously enough?
Fielder H et al. Clin Otolaryngol 1996;21:124–6. SF-36, short form health questionnaire, higher scores
indicate better health. QoL, Quality of Life.

11

Vertigo can be of central or peripheral origin

Central
Involving structures in
the central nervous
system
(e.g., cerebrum,
cerebellum, brainstem)
Peripheral
Involving structures not
part of the central
nervous system, most
frequently the inner ear

Baloh RW. Lancet 1998;352:1841–6. Mukherjee A et al. JAPI 2003;51:1095-101. Puri V, Jones E. J Ky Med Assoc
2001;99:316–21. Salvinelli F et al. Clin Ter 2003;154:341–8. Strupp M, Arbusow V, Curr Opin Neurol 2001;14:11–20.

12

Vertigo of peripheral origin: Conditions &
causes
Condition Details
Benign paroxysmal Brief, position-provoked vertigo episodes caused by
positional vertigo abnormal presence of particles in semicircular canal
Decreasing frequency

Meniere’s disease An excess of endolymph, causing distension of
endolymphatic system
Vestibular neuronitis Vestibular nerve inflammation, most likely due to virus
Acute labyrinthitis Labyrinth inflammation due to viral or bacterial infection
Labyrinthine infarct Compromises blood flow to the labyrinthine
Labyrinthine concussion Damage to the labyrinthine after head trauma
Perilymph fistula Typically caused by labyrinth membrane damage resulting
in perilymph leakage into the middle ear
Autoimmune inner ear Inappropriate immunological response that attacks inner ear
disease cells

Baloh RW. Lancet 1998;352:1841–6. Mukherjee A et al. JAPI 2003;51:1095-101. Parnes LS et al. CMAJ
2003;169:681– 93. Puri V, Jones E. J Ky Med Assoc 2001;99:316–21. Salvinelli F et al. Clin Ter 2003;154:341–8.

13

Vertigo of central origin: Conditions & causes
Condition Details
Migraine Vertigo may precede migraines or occur concurrently
Decreasing frequency

Ischaemia or haemorrhage in vertebrobasilar system can
Vascular disease
affect brainstem or cerebellum function

Demyelination disrupts nerve impulses which can result in
Multiple sclerosis
vertigo

Vertigo resulting from focal epileptic discharges in the
Vestibular epilepsy
temporal or parietal association cortex

Cerebellopontine tumours Benign tumours in the internal auditory meatus

Baloh RW. Lancet 1998;352:1841–6. Mukherjee A et al. JAPI 2003;51:1095-101. Salvinelli F et al. Clin Ter 2003;154:
341–8. Solomon D. Otolaryngol Clin North Am 2000;33:579–601. Strupp M, Arbusow V, Curr Opin Neurol 2001;14:11–20.

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Distinguishing peripheral and central causes of
vertigo
Symptom Likely aetiology
Peripheral Central
Vertigo episodes Mild/moderate Chronic and unremitting

Symptom onset Sudden Gradual

Imbalance Mild/moderate Severe

Nausea, vomiting Severe Varying

Auditory symptoms Common Rare

Neurological symptoms Rare Common

Changes in mental status/ consciousness Infrequent Sometimes

Compensation/resolution Rapid Slow

Baloh RW. Otolaryngol Head Neck Surg 1998;119:55–9. Puri V, Jones E. J Ky Med Assoc 2001;99:316–21.

15

Treatment modalities in vertigo
Pharmacological interventions:
• Anticholinergics
• Antihistamines
• Benzodiazepines
• Calcium channel antagonists (especially verapamil
and nimodipine)
• GABA modulators (like gabapentin and baclofen)
• Neurotransmitter reuptake inhibitors (SSRIs, SNRIs
and tricyclics)
• Nootropics (piracetam)
Troost BT, Arguello LC. Neuro-Otology. In: Bradley WG, Daroff RB, Fenichel GM, Marsden CD, eds. Neurology in Clinical Practice. 3rd ed.
Boston: Butterworth Heinemann;2000:740-742. Oosterveld WJ. Arzneimittelforschung.1980;30(11)1947-1949.

16

Nootropics in Vertigo
Nootropics as a class
• Enhance cognitive processes such as learning and
memory
• Protect and restore cognitive abilities after cerebral insults
• Facilitate interhemispheric flow of information and efficient
tonic cortical/subcortical mechanism
• Do not have sedative or psychostimulant effects
Piracetam, a cyclic derivative of GABA, and the
first nootropic agent
• Alleviates vertigo after head injury/vertigo of central origin
• Significantly decreases the frequency and the severity of
exacerbations in patients with chronic or recurrent vertigo
Balaraman, Shingala J. Indian Journal of Pharmacology. 2002;34(6)439-440
Trkanjec Z, Aleksic-Shibabi A, Demarin V. Rad za medicinske znanosti. 2007;69-73.

17

Treating the cause: pharmacotherapy can
control some vertigo causes
Meniere’s disease
• Diuretics
• Transtympanic gentamicin
Migraine
• Beta-blockers
• Calcium channel blockers
• Tricyclic amines
Vertebrobasilar insufficiency or transient ischaemic
attacks
• Antiplatelet agents

Baloh RW. Lancet 1998;352:1841–6. Goebel JA. Otolaryngol Clin North Am 2000;33:483–93.

18

Treating the cause: a simple particle repositioning
manoeuvre effectively treats most BPPV cases

Modified 3-
position canalith
repositioning
manoeuvre, not
requiring
sedation or skull
vibration
Diagram shows
treatment of
BPPV in the
right ear.

Parnes LS, Agrawal SK, Atlas J. CMAJ 2003;169:681– 93. BPPV, Benign paroxysmal positional vertigo.
Figure reprinted by permission of the publisher. © 2003 CMA Media Inc.

19

Treating the cause: surgery is appropriate in
only a small fraction of vertigo patients
Clinical picture

Patient presents with

Vertigo-inducing tumour Recurrent episodes of acute vertigo due to
(e.g., cerebellopontine tumour) established unilateral vestibular damage
unresponsive to medical therapy

Surgery

Tumour removal Ablative Non-Ablative

Meniere’s disease or Meniere’s disease:
peripheral vestibulopathy: Endolymphatic sac shunt or
Labyrinthectomy decompression
Vestibular nerve section BPPV: Posterior canal occlusion

Goebel JA. Otolaryngol Clin North Am 2000;33:483–93. Salvinelli F et al. Clin Ter 2003;154:341–8.

20

Pharmacotherapy can help manage symptoms
in the short term

Treatments to manage vertigo symptoms
• Vestibular suppressants
 Meclizine, dimenhydrinate, diazepam

• Anti-emetics
 Prochlorperazine, metoclopramide

Side effects include sedation and
extrapyramidal reactions

Baloh RW. Lancet 1998;352:1841–6. Hain TC, Uddin M. CNS Drugs 2003;17:85–100.

21

Rehabilitation exercises can encourage
vestibular adaptation and compensation
Effective recovery from vertigo often requires neural
reorganisation and adaptation
Vestibular rehabilitation exercises aim to promote
adaptation and compensation of the nervous system
They instigate sensory conflicts to promote neural
learning
Rehabilitation exercises are particularly useful when:
• Medical therapy is ineffective
• Patients have poor central integration or motor function

Konnur MK. J Postgrad Med 2000;46:222–3. Mukherjee A et al. JAPI 2003;51:1095–101.

22

There are several types of vestibular
rehabilitation exercises
Vestibular rehabilitation exercises

Visual-vestibular
Head and neck Postural stability
interaction
• Performed lying, sitting or • Promotes visual-vestibular • Improves static and
standing interaction dynamic posture
• Vertigo-provoking • Involves ocular and hand- • Manipulates visual,
movements of head & eye co-ordination exercises somatosensory and
neck in different planes • Uses the vestibulo-ocular vestibular cues
(ex: flexion, extension, reflex • Involves trunk rotation,
etc.) head rotations, and gait
• Uses cervical-ocular reflex exercises

Rehabilitation exercises differ in their target

Konnur MK. J Postgrad Med 2000;46:222–3.

23

Treatment is dependent on vertigo type
Vertigo type Treatment
Peripheral causes
BPPV Canalith repositioning manoeuvre
Labyrinthine concussion Vestibular rehabilitation
Meniere’s disease Low-salt diet, diuretic, surgery, transtympanic gentamicin
Labyrinthitis Antibiotics, removal of infected tissue, vestibular rehabilitation
Perilymph fistula Bed rest, avoidance of straining

Vestibular neuritis Brief course of high-dose steroids, vestibular rehabilitation

Central causes

Migraine Beta-blockers, calcium channel blockers, tricyclic amines

Vascular disease Control of vascular risk factors, e.g., antiplatelet agents

Cerebellopontine tumours Surgery


24

Piracetam: an alternative treatment for vertigo
Theory behind its use


What is Piracetam?
Piracetam:
• is a nootropic drug, acting on cognitive function
without causing sedation or stimulation
• is a cyclic derivative of the neurotransmitter,
γ-aminobutyric acid (GABA)
• has neuronal and vascular effects

Winblad B. CNS Drug Rev 2005; 11(2):169-82

26

Balance requires information of similar intensity
from both vestibular systems
Head movement

Activation of cells in Activation of cells in
left vestibular right vestibular
system system

Central nuclei

10 10

Normally, the input from left and right vestibular system is of
similar intensity (e.g. of size ‘10’)

27

Central vertigo results from a dysfunction in
central processing
Input from left and right vestibular system remains of similar intensity

Central nuclei

10 10

Impaired information transfer between vestibular nuclei causes central
vertigo (e.g. of size ‘10’)

Central vertigo requires central treatment

28

Peripheral vertigo results from a dysfunction in
vestibular system functioning

Central nuclei

5 10

29

Vestibular suppressants suppress vestibular
function in both ears

Central nuclei

5 10
1 2

Vestibular suppressants modify peripheral function bilaterally

30

Piracetam offers an interesting alternative to
existing treatments

Central nuclei

5 10

Piracetam appears to enhance the normal processes of vestibular compensation -
recovery of oculomotor and postural functions - in patients with both peripheral and
central vertigo. Such a mode of action provides a logical approach to symptomatic
treatment, which is distinct from that of other agents, in particular that of vestibular
suppressant agent.
Rosenhall U. et al, Clin. Drug Invest. 1996;11 (5): 251-260.

31

Piracetam’s mode of action:
the membrane hypothesis

Nootropil® (piracetam) interacts
polar head groups with the polar head groups of
phospholipid membranes

- + - +
+ Induces reorganisation of lipid
phospholipid molecules
bilayer

piracetam Formation of mobile drug-
phospholipid complexes

May account for restored
membrane fluidity

Müller WE et al. Pharmacopsychiatr 1999;32(Suppl.1):2–9. Peuvot J et al. Biochem Pharmacol 1995;50:1129–34.

32

Restored membrane fluidity could account for
Piracetam’s efficacy in vertigo
Neuronal effects Vascular effects
• Restored neurotransmission • Enhanced erythrocyte
• Enhanced neuroplasticity deformability
• Improved metabolism • Decreased adhesion of
erythrocytes to endothelial wall
• Facilitation of interhemispheric
information transfer • Prevention of vasospasm
• Normalised platelet
hyperaggregability

Improved neuronal function Improved microcirculation

Facilitates vestibular compensation and adaptation
Adapted from Winblad B. CNS Drug Rev 2005; 11(2):169-82.

33

A number of studies have examined the use of
Piracetam in vertigo
Patients
Study
Author Vertigo type randomised Intervention
period
(completed)
Aantaa Post-concussion 60 (57) Piracetam 2.4 g/d or placebo 8 wks
Deza Bringas Post-concussion 50 (50) Piracetam 4.8 g/d or placebo 8 wks
Hakkarainen Post-concussion 60 (51) Piracetam 4.8 g/d or placebo 8 wks
Dauman Peripheral 20 (20) Piracetam 3 g/d or placebo 30 days
Haguenauer Peripheral 50 (50) Piracetam 2.4 g/d or placebo 60 days
Gavalas1 Central 20 (20) Piracetam 2.4 g/d or placebo 8 wks
Oosterveld* Central 22 (22) Piracetam 2.4 g/d or placebo 4 wks
Rosenhall Central/peripheral 143 (89) Piracetam 2.4 g/d or placebo 8 wks

*Cross over study, 2 weeks of each treatment.

Aantaa. J Int Med Res 1975;3:352–5. Dauman. Les Cahiers d’O.R.L. 1995;4:241–8. Deza Bringas. Revista de
Neuro-Psiquiatria 1984;47:74–86. Gavalas(1). Excerpta Medica 1988;533–8. Gavalas(2). Procs XIXth NES Meeting.
March 1992. Guidetti. Riv Orl Aud Fond 1991;2:148–55. Haguenauer. Les Cahiers d’O.R.L 1986;21:460–6. Hakkarainen.
Eur Neurol 1978;17:50–5. Oosterveld. Arzneimittelforschung 1980;30:1947–9. Rosenhall. Clin Drug Invest 1996;11:251–60.

34

Piracetam eliminates vestibular symptoms in more
patients with peripheral vertigo than placebo
Piracetam 2.4 g/day (n = 25) Placebo (n = 25)

At baseline After 60 days’ treatment

Nystagmus Index Imbalance Star Nystagmus Index Imbalance Star
deviation gait deviation gait

Haguenauer JP. Les Cahiers d’O.R.L 1986;21:460–6.

35

Piracetam significantly reduces frequency and
intensity of vertigo crises

Peripheral vertigo
treated for 60 days
Before the study:
• average of 40 vertigo
episodes per month
• average duration of
vertigo > 6 months

p<0.001 p<0.001

Haguenauer JP. Les Cahiers d’O.R.L 1986;21:460–6. Additional data on file (Oosterveld 2000)

36

Piracetam’s beneficial effect on vertigo persists

without treatment
following treatment cessation

p<0.05
Day 84
Follow-up
Piracetam 2.4 g/day Placebo n = 89

p<0.01
Day 56
treatment
During

Day 28

p<0.01
Adapted from Rosenhall U et al. Clin Drug Invest 1996;11:251–60. Day 84 is 4 weeks after cessation of treatment.

37
number of vertigo episodes

Piracetam rapidly and markedly improves
intensity of unspecified chronic vertigo
Piracetam 3 g/day (n = 10) Placebo (n = 10)
Worse

Vertigo intensity
Better

Percentage improvement in vertigo intensity from baseline to day 15

was significantly greater with Piracetam than placebo (p<0.002)
Dauman R et al. Les Cahiers d’O.R.L. 1995;4:241–8.

38

More patients achieved remission of vertigo
symptoms with Piracetam than placebo
Patients with vertigo of central origin treated for 8 weeks
% patients

Clinician’s assessment of symptoms
Gavalas G et al. Proceedings of the XVth Scientific meeting of the Neurootological and Equilibriometric Society.
Bad Kissingen, 17-20 March 1988. (Excerpta Medica), 533–538. 1988.

39

Fewer patients experience instability between
crises after Piracetam treatment
Patients with chronic, unspecified vertigo of central origin
Piracetam 3 g/day (n = 10) Placebo (n = 10)

p<0.05
% patients without instability

Dauman R et al. Les Cahiers d’O.R.L. 1995;4:241–8

40

Piracetam reduces vertigo-related symptoms
between episodes
Patients with vertigo of varying aetiologies received Piracetam or placebo for 8 weeks


Improvement -16 p<0.001 p<0.01
Change in VAS score (mm)

-12
relative to baseline

-8

-4

Deterioration 0

4 Imbalance Malaise
Symptom severity between vertigo episodes
Rosenhall U et al. Clin Drug Invest 1996;11:251–60.

41

Piracetam:
Efficacy in post-concussion vertigo


Vertigo complaints after head trauma are
common

Dizziness occurs in approximately 50% of
individuals after head or neck injury

Usually due to pathologies in the vestibular,
central nervous system or cervical structures

Friedman JM. Med Health RI 2004;84:296–300

43

Three studies of similar design have been conducted with

PIRACETAM IN POST-CONCUSSION VERTIGO
Aantaa E.
The effect of piracetam upon the late symptoms of patients with head
injuries– 1975
Hakkarainen H, Hakamies L.
Piracetam in the treatment of Post-Concussional Syndrome– 1978
Deza Bringas L.
Treatment of the subjective post-traumatic syndrome with piracetam -
1984
ALL 3 STUDIES WERE:
Double-blind and placebo-controlled
With a 8-week treatment period
Piracetam was administered as either a total dose of 2.4 g/day or
4.8 g/day

Aantaa E, Meurman OH. J Int Med Res 1975;3:352–5; Deza Bringas L. Revista de Neuro-Psiquiatria 1984;47:74–86;
Hakkarainen H, Hakamies L. A double-blind study. Eur Neurol. 1978;17(1):50-5.

44

Results of the 3 studies after 8 weeks

Hakkarainen H,
Aantaa E Deza Bringas L
Hakamies L

Patients analysed (n) 57 51 49

Patients with vertigo at
57/57 (100%) 51/51 (100%) 39/49 (79.6%)
baseline (n%)

Patients on piracetam 24/30 (80%)
22/26 (84.6%) 17/20 (85%)
with improvement in p < 0.01
p <0.05 p < 0.001
vertigo (n%)

Aantaa E, Meurman OH. J Int Med Res. 1975;3:352-5; Deza Bringas L. Revista de Neuro-Psiquiatria. 1984;47:74-86;
Hakkarainen H, Hakamies L. A double-blind study. Eur Neurol. 1978;17(1):50-5.

45

Mechanism of action of piracetam in
post-concussion vertigo

Enhancement of central compensation and
adaptation to vestibular dysfunction
Enhancement of blood flow in the peripheral
and central microcirculation
Improvement of cognitive processes
Improvement of concentration and memory
problems

Guidetti G., Cognition & Nootropics Summit, Athens, 2006.

46

Piracetam: Contraindications & Drug Interactions
[Refer to your local full SPC before prescribing]

Major Contraindications
Piracetam should not be prescribed to patients with cerebral
hemorrhage, end-stage renal impairment. Patients with
Huntington Chorea, hypersensibility to piracetam, or other
pyrrolidone derivatives, or any of the excipients.
Avoid piracetam in pregnant or lactating women
Drug interactions
Piracetam is neither metabolized by the liver nor bound to plasma
albumin. The potential for drug-drug interaction is, therefore, low.
No interactions with sodium valproate have been reported.
There are no known interactions of piracetam with any other
drugs.

Winblad B. CNS Drug Rev 2005;11(2):174.

47

Piracetam: Warnings and common undesirable
effects [Refer to your lcoal full SPC before prescribing]
Warnings
Caution in patients with disorders of hemostasis, major surgery,
or severe haemorrhage
Caution in patients with renal impairment
For long-term treatment in elderly, regular evaluation of Creatinine
clearance is required to allow dosage adaptation if needed

More common undesirable effects
Hyperkinesia, weight increase, nervousness, somnolence,
depression, asthenia.

Winblad B. CNS Drug Rev 2005;11(2):174.

48

- Prescribing Information
NOOTROPIL®
Piracetam Tablets/ Syrup/ Injections
Introduction:
Pharmacotherapeutic group: Nootropics, The active substance, piracetam, is a pyrrolidone (2-oxo-1-pyrrolidine-acetamide), a cyclic derivative of gamma-amino butyric acid (GABA).
Mechanism of action:
Nootropil binds to the polar heads of membrane phospholipids physically in a dose dependent manner. It induces the restoration of the membrane lamellar structure characterized by the formation of mobile drug-phospholipid complexes. This probably
accounts for improved membrane stability, allowing the membrane and transmembrane proteins to maintain or recover their three-dimensional folded structure essential for their function.
Pharmacodynamics:
Nootropil: neuronal and vascular effects
Nootropil exerts its membrane activity in various ways at the level of the neurones. In animals, Nootropil enhances different types of neurotransmission, primarily through postsynaptic modulation of receptor density and activity.
In both animals and man, the functions involved in cognitive processes such as learning, memory, attention and consciousness were enhanced, in the normal subject as well as in deficiency states, without the development of sedative or
psychostimulant effects. Nootropil protects and restores cognitive abilities in animals and humans after various cerebral insults such as hypoxia, intoxications and electroconvulsive therapy. It protects against hypoxia-induced changes in brain function
and performance, as assessed by electroencephalographic (EEG) and psychometric evaluations.
Nootropil exerts its haemorrheological effects on the platelets, red blood cells, and vessel walls by increasing erythrocyte deformability and by decreasing platelet aggregation, erythrocyte adhesion to vessel walls and capillary vasospasm.
Effects on red blood cells
Nootropil improves the deformability of the erythrocyte membrane, decreases blood viscosity and prevents rouleaux formation in patients with sickle cell anemia.
Effects on platelets
Open studies with healthy volunteers and with patients have shown that gradually increasing the dose of Nootropil up to 12 g was associated with a dose-dependent reduction in platelet function compared with pretreatment values (tests of aggregation
induced by ADP, collagen, epinephrine and bTG release), without significant change in platelet count. In these studies, Nootropil prolonged bleeding time. Another study in healthy volunteers did not show any statistically significant difference between
Nootropil (up to 12 g b.i.d) and placebo regarding effects on haemostasis parameters and bleeding time.
Effects on blood vessels
In animal studies, Nootropil inhibited vasospasm and counteracted the effects of various spasmogenic agents. It lacked any vasodilatory action and did induce ‘steal’ phenomenon, nor low or neither reflow, nor hypotensive effects. In healthy volunteers,
Nootropil reduced the adhesion of red blood cells to the vascular endothelium and directly stimulated prostacyclin synthesis in the healthy endothelium.
Effects on coagulation factors
In healthy volunteers, compared with pre-treatment values, Nootropil up to 9.6 g reduced plasma levels of fibrinogen and von Willebrand’s factors (VIII: C; VIII R: AG; VIII R: vW) by 30–40%, and increased bleeding time. In patients with both primary
and secondary Raynaud’s phenomenon, compared with pretreatment values, Nootropil 8 g/d administered over 6 months reduced plasma levels of fibrinogen and von Willebrand’s factors (VIII: C; VIII R: AG; VIII R: vW (RCF)) by 30–40%, reduced
plasma viscosity, and increased bleeding time.
Pharmacokinetics
The pharmacokinetic profile of Nootropil is linear and time-independent with low inter-subject variability over a wide range of doses. This is consistent with its high permeability, high solubility and minimal metabolism. Plasma half-life of Nootropil is 5
hours. It is similar in adult volunteers and in patients. It is increased in elderly patients (primarily due to impaired renal clearance) and in patients with renal impairment. Steady state plasma concentrations are achieved within 3 days of dosing.
Absorption
Nootropil is rapidly and extensively absorbed following oral administration. In fasted subjects, peak plasma concentrations are achieved 1 hour after dosing. The absolute bioavailability of Nootropil oral formulations is close to 100%. Food does not
affect the extent of absorption of Nootropil but it decreases Cmax by 17% and increases tmax from 1 to 1.5 hours. Peak concentrations are typically 84 µg/ml and 115 µg/ml following a single oral dose of 3.2 g and repeat dose of 3.2 g t.i.d., respectively.
Distribution
Nootropil is not bound to plasma proteins and its volume of distribution is approximately 0.6 l/kg. It is known to cross the blood-brain barrier as it has been measured in the cerebrospinal fluid following intravenous administration. In cerebrospinal fluid,
the tmax was achieved at about 5 hours post-dose and the half-life was about 8.5 hours. In animals, NOOTROPIL highest concentrations in the brain were in the cerebral cortex (frontal, parietal and occipital lobes), in the cerebellar cortex and in the
basal ganglia. Nootropil diffuses to all tissues except the adipose tissues. It crosses placental barrier and penetrates the membranes of isolated red blood cells.
Biotransformation
Nootropil is not known to be metabolized in the human body. This lack of metabolism is supported by its lengthy plasma half-life in anuric patients and by the high rate of recovery of the parent compound in the urine.
Elimination
The plasma half-life of Nootropil in adults is about 5 hours following either intravenous or oral administration. The apparent total body clearance is 80–90 ml/min. The major route of excretion is via the urine, accounting for 80–100% of the dose.
Nootropil is excreted by glomerular filtration.
Renal impairment
Nootropil clearance correlated with creatinine clearance. It is therefore recommended that the daily dose of Nootropil is adjusted according to creatinine clearance in patients with renal impairment. In anuric end-stage renal disease patients, the half-life
of Nootropil is increased up to 59 hours. The fractional removal of Nootropil was 50–60% during a typical 4-hour dialysis session.
Hepatic impairment
The effect of hepatic impairment on the pharmacokinetics of Nootropil has not been evaluated. Because 80 to 100% of the dose is excreted in the urine as unchanged drug, hepatic impairment solely would not be expected to have a significant effect on
piracetam elimination.

49

- Prescribing Information
Preclinical safety data
The preclinical data include that piracetam has a low toxicity potential. In vitro and in vivo studies have shown no potential for genotoxicity and carcinogenicity.
Therapeutic indications
In adults
Symptomatic treatment of psycho-organic syndrome whose features, improved by treatment, are memory loss, attention disorders and lack of drive.
Treatment of cortical myoclonus, alone or in combination
Treatment of vertigo and associated disorders of balance, with the exception of dizziness of vasomotor or psychic origin
For prophylaxis and remission of sickle cell vaso-occlusive crises.
In children
Treatment of dyslexia, in combination with appropriate measures such as speech therapy.
For prophylaxis and remission of sickle cell vaso-occlusive crises.
Dosage
Cognitive impairment and post stroke sequelae :
4.8gms per day for 12 weeks.
Cerebrovascular insufficiency
Initiate treatment with 12 IV infusion (as a bolus given over 20 minutes) followed by 3gm IV infusion every 6 hour for at least 2-4 weeks. Further it is followed by 4.8gm orally for at least 12 weeks.
Treatment of myoclonus of cortical origin:
Nootropil is effective within a range of 7.2-24 gm/day. The starting dose could be 7.2 gm/day increasing by 4.8 gm/day every 3 days.
Treatment of vertigo
The recommended dosage of NTP is 2.4- 4.8 gm in BID or TID
Treatment of dyslexia in combination with speech therapy
NTP in 3.3 gm/day in 2 divided doses or 10 ml TID for one full school year
Dosage adjustment
Renal impairment
The daily dose must be individualized according to Creatinine clearance.
Creatinine clearanceSerum creatinine mg/100mlRecommended Dosage60-40 ml/min1.25-1.71/2 usual dosage40-20 ml/min1.7-31/4 usual dosage<20ml/min>3Contraindicated
Adverse drug reactions:
Psychiatric disorders, central and peripheral nervous system disorders, metabolic and nutritional disorders, were found to be associated as adverse effects with Nootropil.
Contraindications
• Hypersensitivity to piracetam or other pyrrolidone derivatives or any of the excipients
• Patients with severe cerebral hemorrhage
• End-stage renal disease patients
Pregnancy and lactation
• Animal studies have not indicated any direct or indirect harmful effects on pregnancy, embryonal/fetal development, parturition or post-natal development.
• Insufficient data are available on the use of Nootropil in pregnant women. Nootropil should not be used during pregnancy unless absolutely necessary.
• Nootropil is excreted in human breast milk and should be avoided during breastfeeding.
PRESENTATION
Nootropil tablets:
Each film coated tablet contains Piracetam 800 mg and 1200 mg. Strip of 30 tablets.
Nootropil Syrup:
Each 5 ml contains Piracetam 500 mg. Bottle of 100 ml.
Nootropil Injection
Each ml contains Piracetam 200 mg. Bottle of 60 ml. Box of 4 ampoules of 15 ml each.
Should any complaint arise, please mention the batch control number indicated on the package.
UCB India Ltd.
133/2, G.I.D.C., Selvas Road,
VAPI 396 195
®Regd. Trade Mark of UCB, Belgium.

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