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784
Advances in Environmental Biology, 5(4): 784-789, 2011
ISSN 1995-0756
This is a refereed journal and all articles are professionally screened and reviewed
ORIGINAL ARTICLE
Comparison of Sedative Effects of Oral Ketamine & Chlorpheniramine in the Manner
of Single and Concomitant administration in Cat
1
Eilyad. Issabeagloo, 2Ali Asghar Gharachorlou, 3Jamshid Ghiasi Ghalahkandi
1
Islamic Azad University- Tabriz branch, Department of Pharmacology, Medical Sciences Faculty. Tabriz, Iran.
Islamic Azad University- Tabriz branch, Department of Basic Sciences, Veterinary Faculty. Tabriz, Iran.
3
Islamic Azad University- shabestar branch, Department of animal Sciences, Veterinary Faculty. shabestar,
Iran.
2
Eilyad. Issabeagloo, Ali Asghar Gharachorlou, Jamshid Ghiasi Ghalahkandi; Comparison of sedative
effects of oral ketamine & chlorpheniramine in the manner of single and concomitant administration
in cat
ABSTRACT
Ketamine is a suitable injectable anesthetic in human and animal that has a low intestinal absorption rate.
It's bioavailability in human by oral administration is %20±7 and by rectal administration in cat is %43.5±6.1
.this drug has some side effects such as hypertension ,histamine releasing effects ,hallucination ,hyper salivation
(specially with oral administration) and etc. Chlorpheniramine is an antihistamine agent that can pass trough
blood-brain barrier and causes CNS suppression. Thereupon it seems that co-administration of Chlorpheniramine
and ketamine cause more effective and deep CNS depression effects. The aim of this study was evaluation of
ketamine and chlorpheniramine CNS suppression effects in the manner of single and together in cat. Ten free
roaming male & mature cats received drugs [ketamine (20, 40, 80mg/kg) & chlorpheniramine (4, 8, 16mg/cat)]
first in mixture of milk (40ml) or meat (30g) or sublingual spray rout. In 2nd stage they received concomitant
doses of chlorpheniramine & ketamine by the method mentioned above. Each animal was observed continually
by educated observer for CNS depression as graded on the behavioral scales. Almost all of the animals rejected
receiving drugs in mixture of milk and meat. So sublingual spray route used for oral administration of drugs.
Chlorpheniramine, alone in sublingual spray administration did not show any significant CNS depression effects
with administered doses. But ketamine showed dose dependent effects in different administered doses.
Concomitant use of chlorpheniramine with ketamine improved depth and duration of ketamine's CNS depression
effects. So results of this study showed this fact that administration of ketamine & chlorpheniramine in mixture
of milk & meat is not a suitable method of administration in cats. But a strong and long time CNS depression
is achieved when ketamine sprayed in mouth (as sublingual form). These effects are more effective in co
administration of these two drugs.
Key words: Ketamine, chlorpheniramine, Sublingual administration, CNS depression, Cat
Introduction
Ketamine (KT) is a synthetic available anesthetic
that has been used in human & animal operations for
almost 35 years. Several studies had showed its wide
margin of safety [3,6]. This agent blocks NMDA (N-
methyl-D-Aspartate) receptors in CNS [5]. KT
induces one form of anesthesia that called
dissociative anesthesia in which there is a marked
sensory loss and analgesia, as well as amnesia and
paralysis of movement, without actual loss of
consciousness [7]. Ketamine has some effects such as
Corresponding Author
Eilyad Issabeagloo, Islamic Azad University- Tabriz branch, Department of Pharmacology,
Medical Sciences Faculty. Tabriz, Iran.
[email protected]
Tell: +989144079927
785
Adv. Environ. Biol., 5(4): 784-789, 2011
sedation, analgesia, and immobility. This drug has
low intestinal absorption rate. It's bioavailability in
human with oral administration is %20±7 [15] and
with rectal administration in cat is %43.5±6/1 [16].
KT was stated to be metabolized to at least two
major compounds of pharmacological interest: to
norketamine (NK) by N-demethylation, which then is
converted to dehydronorketamine (DHNK) by
dehydrogenation [17]. Its major metabolite
norketamine, however, is active with one-third of the
potency of its parent drug as an anesthetic. Thus the
first-pass effect after oral administration results in an
active metabolite that can contribute to the
pharmacological effects.
Oral KT has been used sporadically as
premedication for anesthesia in children [2,18]. Also
it had been administered in fractious cats, when the
animal is hissing [4,8]. KT in anesthetized cats cause
psychotic symptoms, release of histamine and induce
cardiovascular system hyper activity such as increase
of hart rate and hypertension.
Chlorpheniramine is one first generation H1
blockers that not only prevent systemic effects due to
release of histamine but also can induce suppression
of CNS [1]. So it seems that co administration of
Chlorpheniramine with ketamine improves CNS
suppressing effect of KT and decreases some side
effect of this drug (e.g. hyper Salivation). The main
and important aim of this study was evaluation of
CNS suppressing effect of orally administered
ketamine & Chlorpheniramine in the manner of
single and together.
animal was monitored continuously by an educated
experts for CNS depression as graded on the
behavioral scales shown as fallow.
Scales for CNS depression were [14]:
1) No effect
2) impaired gait, prancing gat, some excitement
3) Lowered head, braced stance, hindquarter
weakness
4) Sternal or lateral recumbency, some
responsiveness to repositioning
5) lateral recumbency, no response to movement of
limbs and painful excitements
Reflex to pain in cat is evaluated by painful
excitation of tail or pads with clamp [9].
Also obtained results in administration of various
doses of drugs were evaluated on the base of
underneath parameters for each treatment group: [13].
Onset time of effect, Duration of effect (time
from treatment to recovery), Peak score for each
dose, Percentage of animal reached peak score (lost
the reflexes (upon scores) for each dose), Onset time
of peak score and Duration of peak score.
When ever score 2 recorded we did not
recognize any time to Duration of Peak Score and
onset time of Peak Score.
In second step Chlorpheniramine co-administered
with Ketamine and results evaluated again on the
base of mentioned method. In combination regimes
high dose of each drug with low dose of other, also
middle dose with other's middle dose was used.
Statistical Analysis:
Material and method
Animals: Male & mature stray cats were caged
with free access to food and water, and maintained
on a 12-hour light-dark cycle. The animals were
fasted for 12 hours prior to the study to minimize the
effects of gastric contents on drug absorption rate.
The numbers of cats in treatment groups were ten
animals.
Drugs: Racemic ketamine (ketamine
hydrochloride, Sigma, St. Louis, MO, U.S.A.) was
dissolved in normal saline and the pH of each
solution was adjusted to 5. Ketamine at a dose of 20,
40, 80 mg/kg [8], was administered orally to cats in
mixed with milk (40 cc) or meat (30 g) or sprayed
in sublingual area of mouth by a ordinary syringe
(when animals were rejects the drug in mixture with
milk or meat). For comparison, a similar study was
performed with chlorpheniramine. Chlorpheniramine
as maleate salt (sigma-aldrich, USA) was dissolved
in water as 0.55g/100mL, in 20°C and different doses
of Chlorpheniramine (4, 8, 16mg/cat) (Lowe, 2010)
were administered as a mentioned method. In first
stage, drugs administered separately. Then in 2nd
stage they be used together in treatment groups. Each
The results (Onset Time and Duration of CNS
depressant effects) are expressed as the Mean ± SE.
Differences between the individual mean values in
different groups were analyzed by one-way analysis
of variance (ANOVA) and differences with a p<0.05
were considered significant.
Results:
CNS suppression effect in orally administered
ketamine (20, 40, 80 mg/kg) & Chlorpheniramine (4,
8, 16 mg/cat) in mixture with milk and meat in cat:
In these routes almost all of cats did not accept
drugs in mixture with milk & meat or ice cream or
chocolate. Therefore sublingual method was used
throughout study time.
Rate of CNS suppression of sublingual administration
of Chlorpheniramine (4, 8, 16 mg/cat):
Chlorpheniramine as oral spray in mentioned
doses didn't exert any significant CNS suppression
effect.
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Adv. Environ. Biol., 5(4): 784-789, 2011
Rate of CNS suppression of sublingual administration
of ketamine (20, 40, 80 mg/kg):
shows stronger performance in prolonging of onset
time of CNS suppression effect.
As shown in Tables 1 & 2, Onset time of effect
decreased with increasing dose of ketamine. In dose
of 80 mg/kg this time decreased to 1':24" that in
comparison with ketamine 20 mg/kg was considered
significant) P<0.001).
Also peak score of CNS suppression increased
dose dependently so that in dose 80 mg/kg, in 50%
of cats analgesia was saw (Score5). Onset time of
peak score decreased dose dependently so that in
dose of 80 mg/kg this time reached to 2.59±0.5
minute that in comparison approximatly, is half of
group 20 mg/kg.
Discussion and conclusion:
Rate of CNS suppression in co-administration (as
sublingual method) of ketamine (20, 40, 80 mg/kg)
with Chlorpheniramine (4, 8, 16 mg/cat):
Results of CNS suppression effects of co
administration of ketamine 20 mg/kg +
Chlorpheniramine 16 mg/cat, ketamine 40 mg/kg +
Chlorpheniramine 8 mg/cat, ketamine 80 mg/kg +
Chlorpheniramine 4 mg/cat has been showed in
tables 3 & 4. As saw in table 3 co administration of
Chlorpheniramine with ketamine cause dose
dependently and meaningful accelerating in onset
time of effect & increasing duration of effect in
compare with group ketamine 20mg/kg +
chlorpheniramine 16 mg/cat. Also in compare of
group ketamine 40mg/kg + chlorpheniramine 8mg/cat
with group ketamine 80mg/kg + chlorpheniramine
4mg/cat there is a meaningful accelerating in onset
time of CNS suppression effect so that this effect
depends on ketamine's dose (P<0.05). This effect is
also seen in regard to duration of CNS suppression
within these two groups (P<0.001). Beside peak
score be intensive when ketamine administered dose
increase so that there is a complete anesthesia in
almost 80% of animals in group ketamine 80mg/kg
+ chlorpheniramine 4mg/cat. Also duration of peak
score prolonged whenever ketamine's administered
dose increased.
Comparison of CNS suppression of ketamine (as
sublingual administration) with its and
chlorpheniramine co-administration:
Comparison of CNS suppression effects due to
ketamine in the manner of single administration and
combined with chlorpheniramine are shown in graphs
1 & 2.
Administration of ketamine combined with
chlorpheniramine causes tardier start and also durable
CNS suppression Effect than solely ketamine.
It seems that the administration of ketamine in
combination with higher doses of chlorpheniramine
The results of present study show some notable
facts:
1) Administration of ketamine or chlorpheniramine
as mixed with milk, meat, ice cream or
chocolate is not an appropriate route of
administration of these drugs in cat.
2) Chlorpheniramine didn't cause a significant CNS
suppression effects when sprayed in mouth in
administered doses.
3) Intra oral (sublingual) spray of ketamine in
administrated doses absolutely causes a dose
dependently CNS suppression.
4) CNS depression effect in co administration of
Chlorpheniramine with ketamine improved in
compare with whenever ketamine administered
sporadically.
Ketamine is a drug with high lipid solubility and
rapidly leaves plasma to the CNS (brain). After i.v.
administration, maximum within 1 minute it reaches
to the highest brain concentration. There for this fact
is compatible with its rapid onset time of effect that
seems to be some seconds after IV administration
[10,11]. IV administration of ketamine has some
obvious CNS suppression effects in cat. In the
present study sublingual ketamine spray induced CNS
depression effects in 2.5-3 minutes in cats. These
effects were dose dependently so that with dose of
80 mg/kg the cats reached to score5 (analgesia). This
drug's Rapid onset time of effect with oral
(sublingual) administration, indicates its high mucosal
absorption from proximal parts of GI (e.g. oral cavity
and esophagus).
In other section of this study administration of
chlorpheniramine as intra oral spray didn't exert a
significant CNS suppression effects. This occurrence
is may be due to low or slow distribution of the drug
trough CNS in used doses, low efficacy of drug in
CNS suppression, or etc. so to discover distinct
mechanism of this occurrence further studies may be
needed.
But whenever it added to ketamine's regime (as
oral spray), this drug decreased KT's onset time of
CNS suppression effect. Also severity of CNS
suppression effect (peak score) increased whenever
chlorpheniramine co administered with ketamine.
Parameters of CNS suppression effects (highest
peak score in administered dose and percentage of
animals reached to peak score) were severe and
sensible in group ketamine 80mg/kg +
chlorpheniramine 4mg/cat so as score 5 was seen in
80% of cases in this treatment group. May be slow
onset time of CNS suppression effect in animals that
Adv. Environ. Biol., 5(4): 784-789, 2011
787
Effect of ketamine administration (20, 40, 80 mg/kg as intra oral spray). Onset time and duration of CNS suppression (since
onset time of effect to the time of getting normal) were showed. Results are expressed as Mean±SE.
Dose Of Ketamine (mg/kg)
Onset Time Of Effect (min)
Duration Of Effect (hour)
20
2.26 ± 0.36
0.65 ± 0.09
40
1.65 ± 0.13
1.69 ± 0.31 *
80
1.39 ± 0.11 *
2.63 ± 0.36 ***
*** p<0.001, * p<0.05 significantly different from the control group (Ketamine 20mg/kg).
Table1:
Table 2: Effect of ketamine administration (20, 40, 80 mg/kg as intra oral spray). The highest rate of CNS suppression (Peak Score)
& percentage of cats reached to seen peak score in each dose, also onset time and duration of peak score were showed. Each
group had at least 10 cats. Results are expressed as Mean±SE.
Dose Of
Observed
Percentage Of Animals
Onset Time Of
Duration Of Peak
Ketamine (mg/kg)
Peak Score
Reached Peak Score
Peak Score (min)
Score (min)
20
3
40 %
5.22±0.9
11.15±1.9
4
60 %
3.5±0.5
23.46±6.9
40
3
40 %
4.1±0.38
10.87±2.6
4
60 %
3.1±0.6
62.33±14.9
80
4
50 %
2.23±0.4
86.2±19.8
5
50 %
2.1±0.6
114.4±24.8
Table 3: Effect of ketamine (20, 40, 80 mg/kg) & Chlorpheniramine (4, 8, 16 mg/cat) co administration as sublingual spray. Onset time
and duration of CNS suppression (since onset time of effect to the time of getting normal) were showed. Results are expressed
as Mean±SE.
Ketamine + chlorpheniramine
Onset Time Of Effect (min)
Duration Of Effect (hour)
(mg/kg)
(mg/cat)
20
+
16
3.73 ± 0.31
1.35 ±0.22
40
+
8
3.20 ± 0.28
2.66 ± 0.31*
80
+
4
1.45 ± 0.23**
4.85± 0.42 ***
*P<0.05, **P<0.01, ***P<0.001 significantly different from the control group (Ketamine 20 mg/kg + Chlorpheniramine 16 mg/cat).
Table 4: Effect of ketamine (20, 40, 80 mg/kg) Chlorpheniramine (4, 8, 16 mg/cat) co administration as sublingual spray.
Ketamine + chlorpheniramine
Observed Peak
Percentage Of Animals
Onset Time Of
Duration Of
(mg/kg)
(mg/cat)
Score
Reached Peak Score
Peak Score (min)
Peak Score (hour)
20
+
16
3
20%
9.40±1.1
0.4±0.1
4
80%
7.14±0.57
0.71±0.18
40
+
8
4
60 %
6.03±0.45
1.7±0.3
5
40 %
4.05±0.37
2.02±0.73
80
+
4
4
20 %
3.00±0.6
2.15±0.75
5
80%
2.51±0.58
3.87±0.62
The highest rate of CNS suppression (Peak Score) & percentage of cats reached to seen peak score in each dose, also onset time and
duration of peak score were showed. Each group had at least 10 cats. Results are expressed as Mean±SE.
Graph 1:
Comparison onset time of CNS suppression between ketamine (20, 40, 80 mg/kg) & Ketamine
(20, 40, 80 mg/kg) + Chlorpheniramine (4, 8, 16 mg/cat). Results are expressed as Mean±SE ,
**P<0.01, ***P<0.001.
Adv. Environ. Biol., 5(4): 784-789, 2011
Graph 2:
Comparison duration of CNS suppression between ketamine (20, 40, 80 mg/kg) & Ketamine (20,
40, 80 mg/kg) + Chlorpheniramine (4, 8, 16 mg/cat). Results are expressed as Mean±SE. ***
p<0.001.
received combination of ketamine &
chlorpheniramine in compare with cases treated with
ketamine
alone is due to challenge of
chlorpheniramine with ketamine in mucosal
absorption. But when they reached in brain, CNS
suppression effect is severe due to their synergism.
Chlorpheniramine is one of alkylaminic H1
blockers so that has high oral absorption like other
members of this group and usually cause partial
sedation in treated cases (11). But this drug couldn't
cause any significant sedation in animals may be
because of species diversity or absorption disturbance
in this route or low administration dose or etc. with
attention to this point in present study ketamine and
chlorpheniramine have better results in CNS
suppression in regime ketamine 80mg/kg +
chlorpheniramine 4mg/cat, it seems that this protocol
is suitable to induction deep sedation of cat as non
invasive route of administration. Also more studies
with other antihistamines and or other drugs with
sedative properties as sublingual route in the manner
of single and combine with ketamine is necessary to
achieve a suitable noninvasive anesthetic protocol.
References
1.
2.
3.
788
Katzung, B.G., 2009. basic and clinical
pharmacology, 11th edition. Mc Graw Hill, pp:
276-277.
Ghai, B., R.P. Grandhe, A. Kumar, P. Chari,
2005. Comparative evaluation of midazolam and
ketamine with midazolam alone as oral
premedication. Paediatr Anaesth., 15: 554-9.
Krauss, B., S.M. Green, 2000. Sedation and
analgesia for procedures in children. N.Engl.J.
Med., 342: 938-45.
4. Costa-Farre, C., F. Garcia, A. Andaluz, R.
Torres, F. de Mora, 2005. Effect of H1- and H2receptor antagonists on the hemodynamic
changes induced by the intravenous
administration of ketamine in sevofluraneanesthetized cats. Inflamm Res., 54: 256-60.
5. Freye, E., L.B. Partecke, J.V. Levy, 2005.
Increase in delta- and beta-wave activity of the
EEG during rapid opiate detoxification (ROD)reversal by administration of the non-specific
NMDA-antagonist S+ ketamine-. Neurophysiol
Clin., 35: 25-32.
6. McCarthy, E.C., G.A. Mencio, L.A. Walker et
al., 2000. Ketamine sedation for the reduction of
children's fractures in the emergency department.
J. Bone Joint Surg. Am., 82-A: 912-8.
7. Rang, H.P., M.M. Dale, J.M. Ritter and P.K.
Moore, 2007. Pharmacology. Fifth Edition.
Churchill Livingstone, pp: 533, 547, 607.
8. Richard H. Adams, 2001. Veterinary
Pharmacology and Therapeutics. Iowa State
University. Press / AMES., 3: 252.
9. Ilkiw, J.E., CM. Suter, D. McNeal, T.B. Farver,
E.P. Steffey, 1996. The effect of intravenous
administration of variable-dose midazolam after
fixed-dose ketamine in healthy awake cats. J
Vet Pharmacol Ther., 19(3): 217-24.
10. Ilkiw, J.E., P.J. Pascoe, L.D. Tripp, 2003. Effect
of variable-dose propofol alone and in
combination with two fixed doses of ketamine
for total intravenous anesthesia in cats. Am J
Vet Res., 64: 907-12.
Adv. Environ. Biol., 5(4): 784-789, 2011
11. Ilkiw, J.E., T.B. Farver, C. Suter, D. McNeal,
E.P. Steffey, 2002. The effect of intravenous
administration of variable-dose flumazenil after
fixed-dose ketamine and midazolam in healthy
cats. J Vet Pharmacol Ther., 25: 181-8.
12. Lowe, A.D., 2010. A feline dermatology- cats
are not small dogs – the disease, Fox Valley
Animal Referral Center, 4706 New Horizons
Blvd, Appleton, WI 54914 Swing Into Summer
Seminar.
13. Shimoyama, M., N. Shimoyama, C.E. Inturrisi,
K. Elliott, 1997. Oral ketamine produces a dosedependent CNS depression in the rat. Life Sci.,
60(1): PL9-14.
14. Daniel, M.G., C.E. Ramsay, 2000. Sedative and
physiologic effects of orally administered α2adrenoceptor agonists and Ketamine in Cats.
JAVMA, 216(12).
789
15. White, P.F., J. Schuttler, A. Shafer, D.R.
Stanski, Y. Horai, A.J. Trevor, 1985.
Comparative pharmacology of the ketamine
isomers. Br. J. Anaesth., 57: 197-203.
16. Hanna, R.M., R.E. Borchard, S.L. Schmidt,
1988. Pharmacokinetic of ketamine HCL and
metabolite I in the cat: a comparison of i.v.,
i.m., and rectal administration. J Vet Pharmacol
Ther., 11(1): 84-93.
17. Chang, T., A.J. Glazko, 1974. Biotransformation
and disposition of ketamine. International
Anesthesiology Clinics., 12: 157-177.
18. Darlong, V., D. Shende, M.S. Subramanyam, R.
Sunder, A. Naik, 2004. Oral ketamine or
midazolam or low dose combination for
premedication in children. Anaesth Intensive
Care, 32: 246-9.