5. 5
Anti- emetics
Antihistamines Anti Phenothiazines Miscellaneous
Cholinergics
Large overlap between the effects produced by
antihistamines, anticholinergics and phenothiazines.
6. 6
Phenothiazines
(Prochlorperazine, Thiethylperazine)
Prochlorperazine is less sedating than some other
phenothiazines but drowsiness still occurs
Also causes hypotension, Parkinsonian side effects
--Betts T et al, Brit. J. Clin. Pharmac, 1991, 32, 455-8,
--Curley JWA, E N T Journal, 1984, 65, 555-560
“The drug which most commonly causes
parkinsonism in general practice is
Prochlorperazine”
--Chaplin S, Geriatric Medicine, 1989, Feb, 13-14
7. 7
Anxiolytics (Tranquilizers)
(Benzodiazepines such as diazepam, Lorazepam)
No effect on the underlying vertigo
Helps patient endure the symptoms by allaying anxiety
Many side effects drowsiness and sedation, dependence
and addiction abuse potential, psychomotor
impairment, memory loss, interactions with alcohol
Harris T, Ear Nose Throat J, 1984, 65, 551-5
8. 8
Diuretics
(e.g. Furosemide, Hydrochlorthiazide)
Used in vertigo and meniere’s disease
Reduce the volume of endolymph by promoting
urine flow and reducing fluid retention.
Use mainly associated with electrolyte imbalance
Ludman H, Brit. Med. J., 1981, 282, 454-457, Harris T, Ear Nose Throat J, 1984, 65, 551-5
9. 9
Cinnarizine, Collin Dollery Therapeutic Drugs, C240-3, Godfraind T et al, Drugs of Today, 1982, XVIII(1), 27-42,
Venkataraman S, Neurosciences Today, 1997, Vol. I, 3&4, 205-6, Norre M E, Crit Rev. Phy. Rehab. Med., 1990, 2,2,101-20
Antihistamines
Cinnarizine, Flunarizine, Cyclizine
Drowsiness and blurred vision (Difficult for patients who
drive or operate machinery)
Delay normal vestibular compensation process
Cinnarizine and Flunarizine act via calcium antagonism,
unspecific action may cause side effects
Weight gain & depression (serotonergic effects)
Extrapyramidal symptoms (dopaminergic effects)
G.I. upset
14. 14
Betahistine - Chemistry
Histamine Betahistine
N
N
H
CH2CH2NH2
N
CH2CH2NHCH3
Histamine analogue, can be given orally
with no histamine like side effects
Van Cauwenberge P B, et al, Acta Otolaryngol, 1997, suppl. 526, 43-6,
Venkataraman S, Neurosciences Today, 1998, II, 1 & 2, 56-8
15. 15
Betahistine : Pharmacokinetics
Oral administration
Rapid and complete absorption
Mean plasma half life :- 3-4 Hrs.
Complete excretion via urine in 24 hours
Very low plasma protein binding
One metabolite (2-aminoethyl pyridine) is
found to be active
21. 21
Blocks H3 heteroreceptors
Increases release of other
neurotransmitters e.g. serotonin
Regulates firing activity of
vestibular nuclei
Venkataraman S, Neurosciences Today, 1998, II (1 & 2), 56-8,
Biswas A, Ind. J. Otolaryngol H N S, 1997, 49(2), 179-81
Betahistine - Neurological Effects
22. 22
Betahistine : Mode of action
Blocks
H3 heteroreceptors H3 autoreceptors
stimulates release of other
neurotransmitter e.g. serotonin
Stimulates release of histamine
Regulatory effect on
vestibular nuclei
H1 receptor
Symptomatic relief of
vertigo
Prophylactic effect of vertigo
improvement of cochlear & cerebral blood flow
direct stimulatory effect
24. 24
Betahistine -Tolerance
No sedation
No gastric side effects
No anticholinergic effects
No extrapyramidal side effects
Bradoo RA et al, Ind. J. Otolaryngol HNS, 2000, 52(2), 151-8,
Biswas A, Ind. J. Otolaryngol H N S, 1997, 49(2), 179-81
25. 25
Betahistine: No affinity for
H2 receptors
H2 receptors predominate in stomach
and control gastric secretion
Betahistine has no effect on H2 receptors.
Betahistine is generally free of gastric
side effects
Betahistine, Collin Dollery Therapeutic Drugs, B 62-5
Van Cauwenberge PB, Acta Otolaryngol, 1997, Suppl. 526, 43-6
26. 26
Betahistine
Contraindications - Not known
Precaution / Caution for use
Betahistine, being a histamine analogue,
should be used with caution in patients with
pheochromocytoma, peptic ulcer, bronchial
asthma, concurrent use of antihistamines
Bradoo RA et al, Ind. J. Otolaryngol HNS, 2000, 52(2), 151-8
27. 27
Betahistine No antagonistic effect on
H1 receptors
Antihistamines block H1 receptors in brain, causing
sedation or drowsiness
Betahistine, stimulates H1 receptors
Betahistine, does not slow down vestibular
compensation, unlike antihistamines. Hence is
suitable for use with vestibular habituation therapy.
Kirtane MV, Ind. J. Otolaryngol HNS, 1999, 51(2),27-36
28. 28
Betahistine - Summary
Pharmacokinetics: Rapid and complete absorption
after oral route
Pharmacology: It is a H1 agonist and H3 receptor
antagonist. It increases cochlear and cerebral blood
flow and regulates firing activity of vestibular nuclei.
Dose: 24-48 mg /day
Indication: vertigo, meniere’s syndrome
Contraindications: not known
Precaution for use: pheochromocytoma, peptic ulcer,
bronchial asthma
Editor's Notes
Vertigo patients often have a great fear of vertigo attacks. They are generally scared of attacks in future. They always wish lesser no. of attacks will occur in future & which will be less severe & of shorter duration.
Side effects of Prochlorperazine include
dry mouth, fall in B.P. ( hypoptension), rapid heart beat (Tachycardia), extrapyramidal symptoms (parkinsonism), jaundice (rarely).
Parkinsonism is the most common side effect. In a study of patients referred to a specialist unit in U.K. with drug -induced parkinsonism, 44% cases were due to Prochlorperazine. (Lancet, 1984, ii, 1082-3)
Anxiolytics and tranquilisers have no direct effect on vertigo. They may some patients with vertigo by reliving the underlying anxiety and apprehension. They do not affect pathology of the disease but merely enable the patient to endure the symptoms.
They have a lot of side effects as noted above.
Antihistamines mainly control nausea and vomiting along with vertigo. They have depressive effect on the brain, including the vomiting centre. There are various side effects as given above.
Cinanrizine and Flunarizine are used as antivertigo drugs. They act through calcium antagonistic properties. Their sedating properties affects the patients normal lifestyle.
Betahistine is the original research product of Solvay-Duphar & was first registered in Europe in 1970 for the treatment of Meniere’s disease.
Some of the countries in which Betahistine is available are mentioned below:
Vertin (India)
Betaserc (Belgium, Denmark, Netherlands, U.A.E.etc. )
Serc (France, Spain, U.K.etc. )
Vasomotal (Chile, German Fed. Repub. etc. )
Urutal (Yugoslavia etc. )
More than an estimated 41 million patients have so far been received Betahistine ( as of January 1995). Hence till today this figure must have increased very high.
Chemically, Betahistine is 2-[2-(methylamino)ethyl] pyridine & is formulated as dihydrochloride salt . As shown in the above fig. , there is a close resemblance between the structures of Betahistine & histamine.
Histamine caused a number of side effects & must be administered intravenously to avoid breakdown in liver. Betahistine overcame all these disadvantages since it had no serious side-effects & could be taken orally.
Studies in man using 14-C labeled Betahistine have shown that Betahistine is rapidly absorbed (within 30 min) following oral administration of drug. Plasma radio activity reaches its peak within 1 hour.
Mean half-life was 3-4 hrs. & excretion is virtually complete in urine within 24 hours.
For many years principle mechanism of action of betahistine was believed to be due to its direct agonistic effect on H 1 receptors located in blood vessel of inner ear. This would give rise to local vasodilation and increased permeability.
Recently research is focussed on H3 receptors. H3 receptors are located on th presynaptic membranes of histaminergic and other neurons in the brain. There are two types of H 3 receptors. H3 autoreceptors on histaminergic nerve endings and H3 heterorecpotrs controlling release of other neurotransmitter.
They appear to control the release on histamine and other neurotransmitter by negative feedback mechanism.
Excess Histamine released from nerve endings will bind on presynpatic H 3 receptors. This will inhibit further release of histamine. Thus H3 autoreceptors execute negative feed back control on histamine release.
Betahistine has a powerful antagonistis effects on H 3 autoreceptors. It blocks H3 autorecepotrs so that negative feedback to control histamine release in blocked. Thus more histamine will be released at nerve endings.
This increased amount of histamine released from histaminergic nerve endings can stimulate H1 receptors, thus augmenting direct agonistic effect of Betahistine on these receptors.
Betahistine for past many years is known to be the drug of choice in Meniere’s disease. It is interesting to know that it is effective in various other forms of vertigo. It offers both prophylactic as well as symptomatic effect. Betahistine is also used for vertebrobasilar insufficiency because of its effect on cerebral blood flow.
Clinical studies have shown Betahistine to be well tolerated. The low level of side effects is due to its specific action on H1 & H3 receptors.
Betahistine does not cause sedation / drowsiness which is the classical side effect of many antihistaminic drugs. In fact, Betahistine restores normal lifestyle in patients.
Betahistine does not cause gastric side effects since it has very little affinity for H2 receptors. Betahistine is shown not to increase gastric acid secretion in man.
Betahistine has no anticholinergic action hence it is very unlikely to cause anticholinergic side effects.
Since Betahistine has no antidopaminergic activity, it does not cause extrapyramidal side effects like parkinsonism .
Pheochromocytoma is a rare condition, in which tumors of adrenal glands secrete liberate excess adrenaline and noradrenaline into blood stream causing headcahe, blurred vision, rapid heart beat, raised blood pressure. Histamine is known to stimulate the release of noradrenaline and adrenaline from the tumor. Theoretically, Betahistine being histamine analogue could also make the condition worse. Hence it to be used with caution.
Betahistine, being a histamine analogue,to be used with care in petic ulecr patients.
Intolerance to Betahistine in patients with bronchial asthma is not shown. But care should be taken in bronchial asthma, since Betahistine is a histamine analogue.
