Khot et al., IJPSR, 2013; Vol.

4(3): 900-906 ISSN: 0975-8232

IJPSR (2013), Vol. 4, Issue 3 (Review Article)

Received on 03 November, 2012; received in revised form, 13 February, 2013; accepted, 26 February, 2013

ATHEROSCLEROTIC RISK AMONG EPILEPTIC PATIENTS TAKING CARBAMAZEPINE, PHENYTOIN TREATMENT:

BRIEF REVIEW

S. S. Khot*, Md. Hanif Shaikh and Lalitkumar Gupta

Vadu Rural Health Program, K.E.M. Hospital Research Centre, Sardar Moodliar Rd, Rasta Peth, Pune 411011,
Maharashtra, India
Keywords: ABSTRACT: Epilepsy is a common chronic neurological disorder that requires
Antiepileptic Drugs, Atherosclerosis, long-term or sometimes lifetime therapy. Anticonvulsant drugs are used in
Lipids, Epileptic Children, large quantities during long-term antiepileptic therapy and the treatment
Carbamazepine, Phenytoin
may be associated with various metabolic abnormalities in connective
Correspondence to Author:
tissues, endocrine system and the liver. Recent evidence indicates that
S. S. Khot prolonged use of antiepileptic drugs (AEDs) particularly carbamazepine (CBZ),
phenytoin (PHT) might modify some vascular risk factors; however, the
K.E.M. Hospital Research Centre, influence of AED therapy on the development of atherosclerosis has been
Sardar Moodliar Rd, Rasta Peth, Pune the subject of controversy and pretty unclear. Some epidemiological studies
411011, Maharashtra, India
have reported a higher prevalence of ischemic vascular disease among
E-mail: [email protected] epileptic patients on AEDs, while in other studies the mortality due to
atherosclerosis-related cardiovascular disease in treated epileptics has been
observed to be lower than in the general population. The etiology of
atherosclerosis-related vascular diseases in epileptic patients has not been
fully clarified. Atherosclerotic vascular alterations may start early in life, this
review focuses on major atherogenic risk, including disordered lipid profiles,
and increased lipoprotein (a) serum levels among epileptic patients.

INTRODUCTION: Epilepsy is the most common serious The most common risk factors for epilepsy are
neurological condition and approximately 50 million cerebrovascular disease, brain tumours, alcohol,
people worldwide have it. This neurological disease traumatic head injuries, malformations of cortical
account 1% of global burden of disease (WHO). This development, genetic inheritance, and infections of
equals lung cancer in men and breast cancer in the central nervous system. In resource-poor
women. In India it is estimated to have 60-80 lakhs of countries, endemic infections, such as malaria and
people with epilepsy 1, 2. neurocysticercosis, seem to be major risk factors 8.

In the US, about 100,000 new cases of epilepsy are Multiple epidemiologic studies have shown positive
diagnosed 3, 4. In the UK, between 1 in 140 and 1 in 200 correlations between epilepsy and comorbid vascular
people (at least 300,000 people) are currently being disease. Patients with epilepsy suffer mildly increased
treated for epilepsy 5. Epidemiological studies suggest mortality from ischemic heart disease, with
that between 70 and 80% of people developing standardized mortality ratios (SMRs) between 1.2 and
epilepsy will go into remission, while the remaining 2.5 in several studies in developed countries 9, 10. One
patients continue to have seizures and are refractory Chinese study demonstrated an SMR of 10.7 for
to treatment with the currently available therapies 6, 7. myocardial infarction 11 and comorbid myocardial

Available online on www.ijpsr.com 900

Khot et al., IJPSR, 2013; Vol. 4(3): 900-906 ISSN: 0975-8232

ischemia as reported on death certificates was While the pathway has not been explicitly studied in
positively correlated with epilepsy with an odds ratio humans to our knowledge, this mechanism engenders
of 16 12. Nonfatal ischemic heart disease is also some predictions regarding the effects of certain AEDs
significantly elevated 34% to 63% above controls 13. in patients. For example, an enzyme-inducing AED such
Stronger correlations between epilepsy and as PHT , CBZ should increase serum cholesterol.
cerebrovascular disease are seen, with mortality ratios
3.7 to 5.3 14 and morbidity close to 7 in one study. The On the other hand, valproic acid (VPA), an enzyme-
latter correlation is to be expected, as stroke is a inhibiting medication, should decrease metabolism of
known causative factor for epilepsy. Whether having inter- mediates and increase feedback inhibition,
epilepsy increases subsequent cerebrovascular risk is thereby decreasing production of cholesterol. One
more difficult to demonstrate in the literature, as the might also conjecture that pharmacogenetic
crosssectional nature of most studies makes it difficult heterogeneity of these effects could result in varying
to infer causation. effects of a given AED on lipids in different patients 19.

Very little data exist regarding the effects of specific AED and Atherosclerosis risk: Atherosclerosis is the
AEDs on the incidence of vascular events. One Finnish leading cause of death in the developed world,
study found a lower prevalence of ischemic heart although the true frequency is difficult to accurately
disease in epilepsy patients, and furthermore found determine because it is a predominantly asymptomatic
that patients who were on enzyme-inducing AEDs had condition 20. It is a disease of large and medium-sized
29% lower mortality due to heart disease 15. When a arteries, and is characterized by endothelial dys-
Norwegian group performed a survey of coronary risk function, vascular inflammation, and the presence of
profiles on patients with epilepsy and controls, buildup (fatty streaks) consisting of lipids, calcium, and
however, they found no significant differences 16. cellular debris within the intima of the vessel wall.

It is possible that the Finnish study reflects genetic Some epidemiological studies have indicated that the
variants in the isolated, homogeneous Finnish prevalence and death rates from atherosclerosis
population, as Finnish studies of serologic risk factors related cardiovascular disease (CVD) are slightly
also yield different results than those in other elevated in adult epileptic patients taking antiepileptic
populations. This review focuses on risk of atherogenic drugs (AEDs) 21. However, other studies have come to
metabolic alterations, disordered lipid profiles, and the contrasting conclusion that mortality due to
increased lipoprotein (a) serum levels among epileptic ischemic heart disease appears to be lower in treated
patients on phenytoin, carbamazepine treatment. epileptics than in the general population 22.

Mechanism of Enzyme induction effects on Serum Epidemiological studies in adults with epilepsy have
Cholesterol: The enzyme-inducing AEDs phenytoin found that the risk for ischemic heart disease is
(PHT), carbamazepine (CBZ), increase the activity of the increased by 34%, and the risk for fetal CVD is
hepatic cytochrome P450 system, which is involved in increased by 68% . In a cohort of 9000 patients, once
synthesis of serum cholesterol. Animal data show that hospitalized for epilepsy, a cause-specific mortality
a particular enzyme, CYP51A1, catalyzes the conversion assessment found a standardized mortality ratio of 2.5
of lanosterol into cholesterol intermediates 17. When for ischemic heart disease and 3.5 for stroke. However,
these intermediates build up through inhibition of the in a study of 30–50 year old males, no difference was
enzyme, they in turn inhibit the rate-limiting step of found in the total coronary risk profile between those
cholesterol synthesis, 3-hydroxy-3-methylglutaryl- with epilepsy and controls.
coenzyme A reductase, and slow the synthesis of Thus, the influence of AED therapy on the
cholesterol 18. development of atherosclerosis has been the subject of
It follows that induction of CYP51A1 should therefore controversy, although recent evidence indicates that
increase cholesterol production through metabolism of prolonged antiepileptic treatment might modify some
these intermediates and reduced feedback inhibition. vascular risk factors 23.

Available online on www.ijpsr.com 901

Khot et al., IJPSR, 2013; Vol. 4(3): 900-906 ISSN: 0975-8232

It has been well documented that atherosclerotic comparison. In many studies there were
vascular alterations may start early in life and progress antiepileptic comedications. Studies in children are
with age. The first signs of hyperlipidemia can be difficult to interpret because lipoprotein profiles
detected in childhood 24 and fatty streaks, which are change with increasing age. In addition, it cannot
the earliest pathologic lesions of the atherogenic be completely ruled out that epilepsy itself can
process, can be observed in the aorta and coronary lead to changes in lipoprotein profiles.
arteries of individuals by the age of 20. Thus, recent
studies have focused on the incidence of vascular risk Cholesterol concentrations and especially the ratio
factors and a higher risk of atherosclerosis of LDL-C to HDL-C are relevant determinants for
development among children with epilepsy; however, the incidence and mortality from coronary heart
this link has not yet been firmly established and disease 47, 48. There is some evidence that coronary
remains controversial 25, 26, 27, 28. heart disease is less common in patients with
epilepsy 49 although these data are still uncertain.
Epilepsy is a relatively frequent chronic disorder in CBZ is known to be a powerful inducing agent of
childhood and often requires lifelong therapy. It is cytochrome P-450 enzymes 50, 51 and its effects on
widely suggested that either epilepsy itself or the lipoproteins have been largely attributed to its
prolonged administration of some AEDs is associated enzyme-inducing action. Overall, however, there is
with the undesirable metabolic side effects implicated very little information about the metabolic
in dysfunction of the vessel wall. changes that are responsible for the effects of CBZ
on lipids and no study controlled for confounding
This dysfunction can promote atherogenesis and factors such as diet.
ultimately result in occlusive vascular diseases such as
stroke, myocardial infarction, and peripheral arterial CBZ also induces liver microsomal enzymes,
disease 29, 30, 31. The study conducted by Dechadarevian thereby altering the metabolism of lipids, bile
et al. demonstrated the presence of atherosclerotic acids and bilirubin 52. This leads to alteration in
changes at autopsy of an 11-year-old child who died serum lipid levels and thus affects the
following a status epilepticus who had been treated development of atherosclerosis. Some serum
with carbamazepine (CBZ) for long-standing epilepsy. lipids and apoproteins are atherogenic while
The child had hypercholesterolemia and an over 40% others seem to have an anti-atherogenic effect.
reduction in the vessel lumen diameter due to marked Subjects with high serum HDL-C levels have a low
intimal proliferation and accumulation of foam cells in risk of coronary heart disease, whereas those with
the coronary arteries 32 . high serum TC and LDL-C have increased risk.
However the ratio between the cholesterol
1. Carbamazepine: Carbamazepine (CBZ) is widely fractions (TC/HDL-C; HDL-C/ LDL-C) is a better
used as an anticonvulsant drug in adults and predictor for the development of atherosclerosis.
children. The drug is known to cause multiple Increased HDL-C/ TC and HDL-C/LDL-C is a
metabolic alterations, among them changes in powerful protective factor against atherosclerosis
serum lipoprotein concentrations. The precise while the reverse increases the risk.
frequency and nature of these changes are unclear
as are the underlying mechanisms of action. In There are contradictory reports on the relationship
many studies increased total and/or low-density of antiepileptic drugs to serum lipids. CBZ therapy
lipoprotein cholesterol (LDL-C) concentrations leads to increased serum HDL-C levels, and HDL-
were found, and elevated high-density lipoprotein C/TC ratio also tends to be increased. Muuronen,
cholesterol (HDL-C) is also frequently reported 33- et al. reported that the mortality related to
43
. The interpretation of most studies is limited due atherosclerotic heart disease was lower among
to unsatisfactory study designs; there are very few patients treated with antiepileptic drugs than in
prospective studies 44, 45, 46 whereas all other the general population. They related this finding to
studies were cross-sectional and a variety of the increased levels of HDL-C in these patients.
different control groups were used for

Available online on www.ijpsr.com 902

Khot et al., IJPSR, 2013; Vol. 4(3): 900-906 ISSN: 0975-8232

Some studies have failed to demonstrate a inductive effect of CBZ. The National Child
significant change in serum lipids in patients Education Program in the United States dictates
receiving CBZ monotherapy53. However most that some preventive measures should be taken in
workers have shown significant increase in TC and childhood to prevent premature atherosclerosis.
other lipid fractions in epileptic children receiving
CBZ 54, 55, 56 Franzoni, et al. showed that rise in TC Furthermore, some investigators have
was a result of increased LDL-C levels only. Others recommended avoiding a diet with high
have suggested that the increase in TC is due to cholesterol levels in children treated with CBZ 36, 39.
increase in both LDL-C and HDL-C 57. Similarly, The published data related to the alterations of
there are contradictory reports on the effects of serum lipids resulting from antiepileptic treatment
anticonvulsants on atherogenic ratio (TC/HDL and inducing microsomal enzyme activation, suggest
LDL/HDL ratio). Increased TC/HDL and LDL/HDL that the changes in the serum lipids beyond 3
ratio indicate a higher risk of atherosclerosis. months of treatment could be more significant.

It is suggested that an increase in this ratio, However, larger populations are needed to assess
following CBZ therapy might increase the risk of the relative risk of atherosclerosis caused by the
atherosclerosis. Aggarwal et al., does not show a alterations observed during treatment with CBZ.
significant alteration in TC/HDL and LDL/HDL ratio. Further studies are required to examine the
This result matches with the results of others 38 implication of these changes and the need for
showing no significant difference in TC/HDL-C and preventive measures. Long term prospective
LDL-C/HDL-C ratio in children receiving CBZ. LDL-C studies are required to evaluate the risk of
levels were 33.3% higher in cases compared to atherosclerosis caused by alteration in serum lipid
controls whereas HDL-C levels were 53.3% higher. levels in epileptic patients receiving therapy with
Since HDL-C levels are supposed to be protective, CBZ.
significance of these changes needs to be studied 2. Phenytoin: Phenytoin (PHT) is used as an
further 33. anticonvulsant drug in adults and children. The
Some investigators reported a significant decrease drug is known to cause multiple metabolic
in TC/HDL ratios during the CBZ treatment 19 and alterations, among them changes in serum
some reported a slight increase during the first lipoprotein concentrations. The precise frequency
year of treatment followed by an insignificant and nature of these changes are unclear as are the
decrease 46. This ratio was reported to be underlying mechanisms of action. In many studies
increased 18 and 6 months after the onset of CBZ increased total and/or low-density lipoprotein
treatment in two studies performed in adult and cholesterol (LDL-C) concentrations were found,
pediatric patients, respectively 35, 43 Similarly, and elevated high-density lipoprotein cholesterol
there are contradictory reports on the LDL/HDL (HDL-C) is also frequently reported 58, 59.
ratio in the studies performed in adults45. In particular growing evidence suggests that the
However, the results of the studies performed in older generation AEDs that are commonly used for
the children revealed an increase in this ratio, treatment of epilepsy including phenytoin exert
similar to the results in our CBZ group. In the CBZ prominent effects on the hepatic enzyme system
group, TC/HDL and LDL/HDL ratios greater than and may alter metabolic pathways that are related
the upper limit of normal were more frequent in to increased vascular risk. Recent studies 60, 61
the second and sixth months, respectively, as were indicated that PHT is the potent inducer of the
the levels of TC and LDL. cytochrome P450 (CYP450) system, which exerts
In conclusion, these studies demonstrated that TC, strong effects on serum lipid profile. It follows that
LDL, and the atherogenic ratios increase during this enzyme inducing drug may substantially
treatment with CBZ. In addition, the increase in increase the risk of atherosclerosis.
the level of GGT is thought to be related to the

Available online on www.ijpsr.com 903

Khot et al., IJPSR, 2013; Vol. 4(3): 900-906 ISSN: 0975-8232

Emerging evidence further showed that treatment It is therefore of interest that increase in thickness of
with PHT is significantly associated with increased CCA IMT in monotherapy with PHT and CBZ may be
blood levels of total cholesterol, atherogenic (non related to total cholesterol and LDL-C 63.
HDL) cholesterol and triglycerides 62. Chaung et
al., showed that the increase in thickness of CCA Another investigation found that CBZ-treated patients
IMT in monotherapy with PHT may be related to had higher CA-IMT than VPA-treated patients, who in
total cholesterol and LDL-C 63. Close monitoring of turn had higher CA-IMT than untreated patients with
serum lipid levels and and long-term follow up of epilepsy. When carotid thickness was studied in
patients receiving phenytoin to observe the children treated with VPA alone, treated patients had
incidence of ischemic heart disease is needed to significantly higher CA-IMT without a difference in
obtained clinically significant results. serum lipids 68. CA-IMT in epilepsy patients appears to
be positively correlated with duration of AED therapy
69
Effects of AEDs on Carotid Intima-media thickness: though these investigators did not separate their
Although enzyme-inducing medications appear to findings according to different groups of AEDs.
increase lipids and other serologic markers of vascular
risk, the question remains as to whether these changes These data confirm that enzyme-inducing AEDs may be
in risk markers actually increase the incidence of associated with increased vascular risk over time,
ischemic events in treated patients. Ischemic vascular consistent with their effects on serologsic markers.
disease can have many causes, but if inducer-treated However, they also suggest that VPA might increase
epilepsy patients were truly subject to higher rates of vascular risk through mechanisms unknown. It is
myocardial infarction and stroke from the possible that epilepsy itself might increase vascular
aforementioned serologic alterations, one would risk, which might then be further exacerbated by
expect that vascular disease in these patients would enzymatically active AEDs.
have an atherosclerotic etiology. Future studies are needed to compare CA-IMT
Carotid intima-media thickness (CA-IMT) as assessed between those treated with newer-generation non-
by ultrasound is considered to be a surrogate measure enzyme-inducing agents such as levetiracetam,
of atherogenesis and has been strongly correlated with lamotrigine, and topiramate.
risk of both stroke and myocardial infarction in several CONCLUSION: The risk of vascular complications from
prospective studies 64, 65, 66. One study of patients AED therapy is an area of legitimate concern in need of
treated mainly with enzyme-inducing drugs showed further study. Enzyme-inducing AEDs in particular may
higher CA-IMT relative to controls 67. pose a risk by increasing atherogenic serum cholesterol
Chaung et al., also demonstrated that the duration of fractions. AED may also have adverse long-term
monotherapy with CBZ & PHT is significantly associated metabolic consequences, including obesity, insulin
with acceleration of atherosclerosis in patients with resistance, and the metabolic syndrome.
epilepsy, via different underlying mechanism. Pharmacoepidemiologic studies are needed to
Dyslipidemia has long long been known to be determine the long-term vascular effects of
important risk factors for atherosclerosis. carbamazepine and phenytoin. Because patients with
LDL-C plays an important role in the atherosclerotic epilepsy require medication for years, and often for
process by increasing endothelial permeability, life, it is difficult to justify the long-term use of these
retention of lipoproteins within the intima of blood agents when there are capable alternatives. Many of
vessel, recruitment of inflammatory cells and the adverse effects of the older drugs appear to be
formation of foam cells. Emerging evidence further rapidly reversible, prompting consideration of whether
showed that treatment with enzyme inducing AED’s patients who are currently treated with these agents
such as CBZ and PHT, is significantly associated with should be switched to alternative therapies, even in
increased blood levels of total cholesterol, atherogenic the absence of obvious side effects.
cholesterol, triglyceride and tHCY.

Available online on www.ijpsr.com 904

Khot et al., IJPSR, 2013; Vol. 4(3): 900-906 ISSN: 0975-8232

Newer medications without effects on hepatic 21. Elliott JO, Jacobson MP, Haneef Z. Cardiovascular risk factors
and homocysteine in epilepsy. Epilepsy Res 2007; 76:113-123.
enzymes likely do not have these chronic metabolic 22. Kaste M, Muuronen A, Nikkila EA, Neuvonen PJ. Increase of low
consequences, and we recommend their use over serum concentrations of high-density lipoprotein (HDL)
older-generation drugs whenever possible. cholesterol in TIA-patients treated with phenytoin. Stroke 1983;
14:525-530.
23. Tumer L, Serdaroglu A, Hasanoglu A, Biberoglu G, Aksoy E.
REFERENCES: Plasma homocysteine and lipoprotein (a) levels as risk factors
for atherosclerotic vascular disease in epileptic children taking
1. Srinivas HV. Epilepsy: the future scenario. Ann Indian Acad
anticonvulsants. Acta Paediatr 2002; 91:923-926.
Neurol 2010; 31:2-5.
24. Strong JP, Zieske AW, Malcom GT. Lipoproteins and
2. Sander JW. The epidemiology of epilepsy revisited. Curr Opin
atherosclerosis in children: an early marriage? Nutr Metab
Neurol 2003; 16:165-170.
Cardiovasc Dis 2001; 11:16-22.
3. Begley CE, Annegers JF, Lairson LB, Reynolds TF. Epilepsy
25. Demircioglu S, Soylu A, Diric E. Carbamazepine and valproic
incidence, prognosis, and use of medical care in Houston, Texas,
acid: effects on the serum lipids and liver functions in children.
and Rochester,Minnesota. Epilepsia 1998; 39(6):222.
Pediatr Neurol 2000; 23:142-146.
4. Annegers JF. Epidemiology of epilepsy. In: Wyllie E, editor. The
26. Huemer M, Ausserer B, Graninger G, Hubmann M, Huemer C,
treatment of epilepsy: principles and practice. 2nd ed.
Schlachter K, Tscharre A. Hyperhomocysteinemia in children
Baltimore: Williams & Wilkins 1997; 165-172.
treated with antiepileptic drugs is normalized by folic acid
5. Yuen AW, Sander JW. Is omega-3 fatty acid deficiency a factor
supplementation. Epilepsia 2005; 46:1677-1683.
contributing to refractory seizures and SUDEP? A hypothesis.
27. Reddy MN. Effect of anticonvulsant drugs on plasma total
Seizure 2004; 13:104-107.
cholesterol, high-density lipoprotein cholesterol, and
6. Kwan P, Sander JW. The natural history of epilepsy: an
apolipoproteins A and B in children with epilepsy. Proc Soc Exp
epidemiological view. J Neurol Neurosurg Psychiatry 2004;
Biol Med 1985; 180:359–363.
75:1376-1381.
28. Verrotti A, Pascarella R, Trotta D, Giuva T, Morgese G, Chiarelli
7. Halatchev VN. Epidemiology of epilepsy--recent achievements
F. Hyperhomocysteinemia in children treated with sodium
and future. Folia Medica (Plovdiv) 2000; 42:17-22.
valproate and carbamazepine. Epilepsy Res 2000; 41:253–257.
8. Duncan JS, Sander JW, Sisodiya SM, Walker MC. Adult epilepsy.
29. Dasheiff RM, Sudden unexpected death in epilepsy: a series
Lancet 2006; 367:1087-1100.
from an epilepsy surgery program and speculation on the
9. Annegers JF, Hauser WA, Shirts SB. Heart disease mortality and
relationship to sudden cardiac death. J Clin Neurophysiol 1991;
morbidity in patients with epilepsy. Epilepsia 1984; 25:699-704.
8:216–222.
10. Nilsson L, Tomson T, Farahmand BY, Diwan V, Persson PG.
30. Hamed S, Hamed E, Hamdy R, Nabeshima T. Vascular risk
Cause-specific mortality in epilepsy: a cohort study of more
factors and oxidative stress as independent predictors of
than 9,000 patients once hospitalized for epilepsy. Epilepsia
asymptomatic atherosclerosis in adult patients with epilepsy.
1997; 38:1062-1068.
Epilepsy Research 2007; 74:183-192.
11. Ding D, Wang W, Wu J, Ma G, Dai X, Yang B, et al. Premature
31. Hamed SA, Nabeshima T. The high atherosclerotic risk among
mortality in people with epilepsy in rural China: a prospective
epileptics: the atheroprotective role of multivitamins. J
study. Lancet Neurol 2006; 5:823–827.
Pharmacol Sci 2005; 98:340-353.
12. Satishchandra P, Chandra V, Schoenberg BS. Case-control study
32. Dechadarevian J, Legido A, Miles D, Katsetos, C. Epilepsy,
of associated conditions at the time of death in patients with
atherosclerosis, myocardial infarction, and carbamazepine. J
epilepsy. Neuroepidemiology 1988; 7:109-114.
Child Neurol 2003; 18:150-151.
13. Gaitatzis A, Carroll K, Majeed AW, Sander J. The epidemiology
33. Aggarwal A, Kumar M, Faridi MMA. Effect of carbamazepine on
of the comorbidity of epilepsy in the general population.
serum lipids and liver function tests. Indian Pediatrics 2005;
Epilepsia 2004; 45:1613-1622.
42:913-918
14. Cockerell OC, Johnson AL, Sander JW, Hart YM, Goodridge DM,
34. Sudhop T, Bauer J, Elger CE, Von BK. Increased high-density
Shorvon SD. Mortality from epilepsy: results from a prospective
lipoprotein cholesterol in patients with epilepsy treated with
population-based study. Lancet 1994; 344:918–921.
carbamazepine: a gender-related study. Epilepsia 1999; 40:480-
15. Muuronen A, Kaste M, Nikkila EA, Tolppanen EM. Mortality
484.
from ischaemic heart disease among patients using
35. Sozuer DT, Atakil D, Dogu O, Baybas S, Arpaci B. Serum lipids in
anticonvulsive drugs: a case-control study. Br Med J.1985;
epileptic children treated with carbamazepine and valproate.
23:1481-1483.
Eur J Pediatr 1997; 156:565–567.
16. Nakken KO, Kornstad S. Do males 30–50 years of age with
36. Verrotti A, Domizio S, Angelozzi B, Sabatino G, Morgese G,
chronic epilepsy and on long-term anticonvulsant medication
Chiarelli F. Changes in serum lipids and lipoproteins in epileptic
have lower-than-expected risk of developing coronary heart
children treated with anticonvulsants. J Pediatr Child Health
disease? Epilepsia 1988; 39:326-330.
1997; 33:242-245.
17. Gibbons GF. The role of cytochrome P450 in the regulation of
37. Yalcin E, Hassanzadeh A, Mawlud K. The effects of long-term
cholesterol biosynthesis. Lipids 2002; 37:1163–1170.
anticonvulsive treatment on serum lipid profile. Acta Paediatr
18. Kandutsch AA, Chen HW. Inhibition of cholesterol synthesis by
Jpn 1997; 39:342–345.
oxygenated sterols. Lipids 1978; 13:704–707.
38. Eiris JM, Lojo S, Del Rio MC. Effects of long-term treatment with
19. Khoury LP, Mintzer S. Antiepileptic Drugs and Markers Of
antiepileptic drugs on serum lipid levels in children with
Vascular Risk. Current Treat Option Neurol 2011; 12(4):300-308.
epilepsy. Neurology 1995; 45:1155–1157.
20. Berenson GS, Srinivasan SR, Bao W, Newman WP, Tracy RE,
39. Franzoni E, Govoni MD, Addato S, Gualandi S, Sangiorgi Z,
Wattigney WA. Association between multiple cardiovascular
Descovich GC. Total cholesterol, high density lipoprotein
risk factors and atherosclerosis in children and young adults.
The Bogalusa Heart Study. N Engl J Med 1998; 338:1650-1656.

Available online on www.ijpsr.com 905

Khot et al., IJPSR, 2013; Vol. 4(3): 900-906 ISSN: 0975-8232

cholesterol and triglycerides in children receiving antiepileptic 55. Nikolaos T, Stylianos G, Chryssoula N, Irini P, Christos M,
drugs. Epilepsia 1992; 33:932-935. Dimitrios T, 2004. The effect of long-term antiepileptic
40. Luoma PV, Myllyla VV, Sotaniemi EA, Lehtinen IA, Hokkanen EJ. treatment on serum cholesterol (TC, HDL, LDL) and triglyceride
Plasma high-density lipoprotein cholesterol in epileptics treated levels in adult epileptic patients on monotherepy. Med Sci
with various anticonvulsants. Eur Neurol 1980;19: 67–72 Monit 2004; 10:MT50-MT52.
41. Luoma PV, Sontaniemi EA, Pelkonen RO, Ehnholm C. High- 56. Bramswig S, Sudhop T, Luers C, Von-Bergman K, Berthhold HK.
density lipoproteins and hepatic microsomal enzyme induction Lipoprotein A concentration increases during treatment with
in alcohol consumers. Res Commun Chem Pathol Pharmacol carbamazepine. Epilepsia 2003; 44:457-460.
1982; 37:91-96. 57. Eiris JM, Rodriguez IN, Rio MD, Mesegaer P, Rio MC, Gago MC.
42. Reddy MN. Effect of anticonvulsant drugs on plasma total The effects on lipid and apolipoprotein serum levels of long-
cholesterol, high-density lipoprotein cholesterol, and term carbamazepine, valproic acid and phenobarbital therapy
apolipoproteins A and B in children with epilepsy. Proc Soc Exp in children with epilepsy. Epilepsy Res 2000; 41:1-7.
Biol Med.1985; 180:359–363. 58. Dewan P, Aggarwal A, Afaridi MM. Effect of phenytoin and
43. Zeilthofer S, Doppelbauer A, Tribl G, Leitha T, Deecke L. Changes valproic acid therapy on serum lipid level and liver function
in serum lipid pattern during long term anticonvulsant tests. Indian Pediatrics 2008; 45:855-858.
treatment. Clin Invest 1993; 71:574-578. 59. Kaste M, Muuronen A, Nikkila EA, Neuvonen PJ. 1983. Increase
44. Brown DW, Ketter TA, Crumlish J, Post RM.Carbamazepine- of low serum concentrations of high-density lipoprotein (HDL)
induced increases in total serum cholesterol: clinical and cholesterol in TIA-patients treated with phenytoin. Stroke 1983;
theoretical implications. J Clin Psychopharmacol 1992; 12:431- 14:525–530.
437. 60. Mintzer S, Mattson RT. Should enzyme-inducing antiepileptic
45. Heldenberg D, Harel S, Holtzman M, Levtow O, Tamir I. The drugs be considered first-line agents? Epilepsia 2009; 50(8):42–
effect of chronic anticonvulsant therapy on serum lipids and 50.
lipoproteins in epileptic children. Neurology 1983; 33:510–513. 61. Belcastro V, Striano P, Gorgone G, Costa C, et al.,
46. Isojarvi JI, Pakarinen AJ, Myllyla VV.Serum lipid levels during Hyperhomocysteinemia in epileptic patients on new
carbamazepine medication: a prospective study. Arch Neurol antiepileptic drugs. Epilepsia 2010; 5(1):274–279.
1993; 50:590–593. 62. Svalheim S, Luef G, Rauchenzauner M, Morkrid L, Gjerstad L,
47. Assmann, G, Funke H. HDL metabolism and atherosclerosis. J Tauboll E, Cardiovascular risk factors in epilepsy patients taking
Cardiovasc Pharmacol 1990; 16(9): S15–S20. levetiracetam, carbamazepine or lamotrigine. Acta Neurol
48. Castelli WP, Garrison RJ,Wilson PW,Abbott RD, Kalousdian S, Scand 2010; 122(190):30–33.
Kannel WB.Incidence of coronary heart disease and lipoprotein 63. Chaung, Y.C., Chaung, H.Y., et al., 2012. Effects of long term
levels. JAMA 1986; 256:2835-2838. antiepileptic drug monotherapy on vascular risk factors and
49. Livingston S. Phenytoin and serum cholesterol. Br Med J 1976; atherosclerosis. Epilepsia 53 (1), 120-128.
586–586. 64. O’Leary DH, Polak JF, Kronmal RA, et al. Cardiovascular Health
50. Isojarvi JI, Pakarinen AJ, Rautio A, Pelkonen O, Myllyla VV.Liver Study Collaborative Research Group. Carotidartery intima and
enzyme induction and serum lipid levels after replacement of media thickness as a risk factor for myocardial infarction and
carbamazepine with oxacarbazepine. Epilepsia 1994; 35:1217- stroke in older adults. N Engl J Med 1999; 340:14–22.
1220. 65. Lorenz MW, Kegler S, Steinmetz H. Carotid intima-media
51. Pirmohamed M, Kitteringham NR, Breckenridge AM, Park BK. thickening indicates a higher vascular risk across a wide age
The effect of enzyme induction on the cytochrome P450- range: prospective data from the Carotid Atherosclerosis
mediated bioactivation of carbamazepine by mouse liver Progression Study (CAPS). Stroke 2006; 37:87–92.
microsomes. Biochem Pharmacol 1992; 44:2307-2314. 66. Silvestrini M, Cagnetti C, Pasqualetti P, et al. Carotid wall
52. Havel RJ, Kane JP. Structure and metabolism of plasma thickness and stroke risk in patients with asymptomatic internal
lipoproteins.In: Secriver CR, Beaudet, A.L., Sly W.S., Valle, D., carotid stenosis. Atherosclerosis. 2010; 210(2):452-457.
(eds). The Metabolic and Molecular Basis of Inherited Disease, 67. Schwaninger M, Ringleb P, Annecke A, et al. Elevated plasma
7th edn, vol II. New York, McGraw-Hill, 1995; 1841-1851. concentrations of lipoprotein(a) in medicated epileptic patients.
53. Deda G, Caksen H, Icagasioglu D. Effect of long term J Neurol 2000; 247:687–690.
carbamazepine therepy on serum lipids, vitamin B12 and folic 68. Erdemir A, Cullu N, Yis U, et al. Evaluation of serum lipids and
acid level in children. J Pediatr Endocrinol Metab 2003; 16:193- carotid artery intima media thickness in epileptic children
196. treated with valproic acid. Brain Dev 2009; 31:713–716.
54. Yilmaz E, Dosan Y, Gurgoze MK, Gungor S. Serum lipid changes 69. Tan TY, Lu CH, Chaung HY, Lin TK, Liou CW, Chang WN et al.,
during anticonvulsive treatment in epileptic children. Acta Long term antiepileptic drug therapy contributes to the
Neurol Belg. 2001; 101:217-220. acceleration of atherosclerosis. Epilepsia 2009; 50(6):1579-
1586.

How to cite this article:

Khot SS, Shaikh H and G. Lalitkumar: Atherosclerotic risk among Epileptic patients taking Carbamazepine, Phenytoin treatment: A
Brief Review. Int J Pharm Sci Res. 2013; 4(3); 900-906.

Available online on www.ijpsr.com 906