Antiepileptics + Antineoplastics; Cytotoxic - Drug Interactions

Carbamazepine, phenytoin and valproate serum levels can be reduced by several antineoplastic drug regimens and seizures canoccur if antiepileptic dosages are not raised appropriately. Incontrast,phenytoin toxicity has occurred when fluorouracil andfluorouracil prodrugs, such as capecitabine, doxifluridine and tegafur, were given. The effects of many antineoplastics are reduced or changed by enzyme-inducing antiepileptics. Increasedhaematological toxicity may occur if valproate is given with fotemustine and cisplatin.

There are a number of reports (mainly case reports) that implicate a variety of types of chemotherapy in reducing levels of carbamazepine, phenytoin, and valproate. See table 1 below, for details.

Two epileptic patients taking phenytoin developed phenytoin toxicity when they were given fluorouracil to treat colon cancer (See reference number 1,2). Three patients with malignant brain tumours developed acute phenytoin toxicity associated with raised serum phenytoin levels when they were given UFT (uracil and tegafur,a prodrug of fluorouracil) (See reference number 3). Another case of phenytoin toxicity has been reported with UFT (See reference number 4). Phenytoin toxicity was also seen in a woman treated with combination therapy that included fluorouracil prodrug doxifluridine (See reference number 5). Similarly,phenytoin toxicity has occurred in a patient given capecitabine (another prodrug of fluorouracil) (See reference number 6). Although in one report,(See reference number 3) no interaction occurred in one of patients when UFT was replaced by fluorouracil, cases of phenytoin toxicity have been reported in 3 patients receiving fluorouracil with folinic

A retrospective study reviewed effects of 3 or more cycles of 72 hrs of carmustine and cisplatin chemotherapy in 19 patients who did not vomit. A phenytoin dose increase was required in three-quarters of patients, which was, on average, 40 % of original dose (range 20 to 100%). The effect on phenytoin levels persisted after chemotherapy had finished, with levels returning to normal 2 to 3 weeks later.

Estimated phenytoin level 15 micrograms/mL,but level only reached 2 micrograms/mL. Patient fitted.

After chemotherapy same dose produced a toxic level of 42

Papillary adenocarcinoma of ovaries

Seizures occurred 2 to 3 days after starting chemotherapy. All drug levels dropped to one-third or lower. Doses increased to compensate, which led to phenytoin toxicity when chemotherapy finished.

Phenytoin level dropped from 9.7 to 4.6 micrograms/mL 10 days into chemotherapy,resulting in seizures. Phenytoin dose had to be increased by 35 % to achieve a level of 10.7 micrograms/mL.

Increasing dose from 30 to 50 mg/kg per day prevented subtherapeutic levels

8 micrograms/mL on day before chemotherapy to 3.6 micrograms/mL on 6th day of chemotherapy

Dose of phenytoin had to be increased by 50 to 300 % in 10 patients to maintain phenytoin levels in therapeutic range

CSF valproic acid levels reduced by 70 % during perfusion, but returned to normal levels within 7 hours.

Serum valproate levels reduced by 50 % after first cycle and generalised tonic-clonic seizures occurred

Grossman SA,Sheidler VR, Gilbert MR. Decreased phenytoin levels in patients receiving chemotherapy. Am J Med (1989) 87,505–10.

Sylvester RK,Lewis FB, Caldwell KC, Lobell M, Perri R, Sawchuk RA. Impaired phenytoin bioavailability secondary to cisplatinum,vinblastine, and bleomycin. Ther Drug Monit (1984) 6,302-5.

Fincham RW,Schottelius DD. Case report. Decreased phenytoin levels in antineoplastic therapy. Ther Drug Monit (1979) 1,277-83.

Bollini P,Riva R, Albani F, Ida N, Cacciari L, Bollini C, Baruzzi A. Decreased phenytoin level during antineoplastic therapy: a case report. Epilepsia (1983) 24,75-8.

Neef C,de Voogd-van der Straaten I. An interaction between cytostatic and anticonvulsant drugs. Clin Pharmacol Ther (1988) 43,372-5.

Dofferhoff ASM,Berensen HH, Naalt Jvd, Haaxma-Reiche H, Smit EF, Postmus PE. Decreased phenytoin level after carboplatin treatment. Am J Med (1990) 89,247-8.

Gattis WA,May DB. Possible interaction involving phenytoin,dexamethasone, and antineoplastic agents: a case report and review. Ann Pharmacother (1996) 30,520-6.

Nahum MP,Ben Arush MW, Robinson E. Reduced plasma carbamazepine level during chemotherapy in a child with malignant lymphoma. Acta Paediatr Scand (1990) 79,873-5.

Jarosinski PF,Moscow JA, Alexander MS, Lesko LJ, Balis FM, Poplack DG. Altered phenytoin clearance during intensive treatment for acute lymphoblastic leukemia. J Pediatr (1988) 112,996-9.

Ghosh C,Lazarus HM, Hewlett JS, Creger RJ. Fluctuation of serum phenytoin concentrations during autologous bone marrow transplant for primary central nervous system tumors. J Neurooncol (1992) 12,25-32.

Schrøder H,Østergaard JR. Interference of high-dose methotrexate in metabolism of valproate? Pediatr Hematol Oncol (1994) 11, 445-9.

Morikawa N,Mori T, Abe T, Kawashima H, Takeyama M, Hori S. Pharmacokinetics of cytosine arabinoside,methotrexate, nimustine and valproic acid in cerebrospinal fluid during cerebrospinal fluid perfusion chemotherapy. Biol Pharm Bull (2000) 23,784-7.

Ikeda H,Murakami T, Takano M, Usui T, Kihira K. Pharmacokinetic interaction on valproic acid and recurrence of epileptic seizures during chemotherapy in an epileptic patient. Br J Clin Pharmacol (2005) 59,593-7.

A number of antiepileptic drugs affect levels of various antineoplastics

Anthracyclines; Doxorubicin + Barbiturates interaction,

Busulfan + Phenytoin interaction,

Cyclophosphamide or Ifosfamide + Barbiturates interaction,

Cyclophosphamide or Ifosfamide + Phenytoin interaction,

Etoposide + Antiepileptics interaction,

Imatinib + CYP3A4 inducers interaction,

Irinotecan + Antiepileptics interaction,

Methotrexate + Antiepileptics interaction,

Procarbazine + Antiepileptics interaction,

Streptozocin + Phenytoin interaction,

Taxanes; Paclitaxel + Antiepileptics interaction,

Teniposide + Antiepileptics interaction,

Topotecan + Phenytoin interaction,

Not fully understood, but a suggested reason for fall in serum antiepileptic levels is that these antineoplastics damage intestinal wall, which reduces absorption of antiepileptic. Other mechanisms may also have some part to play. The raised serum phenytoin levels possibly occur because liver metabolism of phenytoin is reduced by these antineoplastics. Changes in plasma protein binding may also have been involved.

Information is scattered and incomplete. However,it appears that both altered antiepileptic levels and altered antineoplastic levels can occur, possibly leading to loss of efficacy or toxicity. Where possible,it may be prudent to avoid concurrent use of enzyme-inducing antiepileptics and antineoplastics. If this is not possible, serum antiepileptic levels should be closely monitored during treatment with any of these antineoplastics, making dosage adjustments as necessary, and efficacy of antineoplastics should also be closely monitored.

Gilbar PJ,Brodribb TR. Phenytoin and fluorouracil interaction. Ann Pharmacother (2001) 35, 1367–70.

Rosemergy I,Findlay M. Phenytoin toxicity as a result of 5-fluorouracil administration. N Z Med J (2002) 115, U124.

Wakisaka S,Shimauchi M, Kaji Y, Nonaka A, Kinoshita K. Acute phenytoin intoxication associated with the antineoplastic agent UFT. Fukuoka Igaku Zasshi (1990) 81, 192–6.

Table 1 Reduced antiepileptic levels during antineoplastic therapy
Antiepileptic Antineoplastic Malignancy Outcome Refs
Phenytoin Cisplatin Carmustine Brain tumours A retrospective study reviewed the effects of 3 or more cycles of 72 hrs of carmustine and cisplatin chemotherapy in 19 patients who did not vomit. A phenytoin dose increase was required in three-quarters of patients, which was, on average, 40 % of the original dose (range 20 to 100%). The effect on phenytoin levels persisted after the chemotherapy had finished, with levels returning to normal 2 to 3 weeks later. 1
Phenytoin Cisplatin Vinblastine Bleomycin Metastatic germ cell tumour Estimated phenytoin level 15 micrograms/mL, but level only reached 2 micrograms/mL. Patient fitted. 2
Phenytoin Primidone Cisplatin Vinblastine Bleomycin Metastatic embryonal cell cancer Phenytoin 800mg daily gave a level of 15 micrograms/mL whilst receiving chemotherapy. After chemotherapy the same dose produced a toxic level of 42.8 micrograms/mL. Phenobarbital levels unaffected. 3
Phenytoin Phenobarbital Vinblastine Carmustine Methotrexate Lung cancer with brain metastases Phenytoin levels fell from 9.4 to 5.6 micrograms/mL 24 hrs after vinblastine. Patient fitted. Phenytoin levels returned to normal 2 weeks after chemotherapy. Phenobarbital levels unaffected. 4
Phenytoin Carbamazepine Sodium valproate Doxorubicin Cisplatin Cyclophosphamide Altretamine Papillary adenocarcinoma of the ovaries Seizures occurred 2 to 3 days after starting chemotherapy. All drug levels dropped to one-third or lower. Doses increased to compensate, which led to phenytoin toxicity when the chemotherapy finished. 5
Phenytoin Carboplatin Small cell lung cancer with brain metastases Phenytoin level dropped from 9.7 to 4.6 micrograms/mL 10 days into chemotherapy, resulting in seizures. Phenytoin dose had to be increased by 35 % to achieve a level of 10.7 micrograms/mL. 6
Phenytoin Dacarbazine Carmustine Cisplatin Tamoxifen Malignant melanoma with brain metastases Phenytoin level of only 2.5 micrograms/mL despite a loading 1-g dose and a daily dose of 500mg phenytoin. 7
Phenytoin followed by Carbamazepine Vincristine Cytarabine Hydroxycarbamide Daunorubicin Methotrexate Tioguanine Cyclophosphamide Carmustine Stage IV T-cell lymphoma Phenytoin failed to reach therapeutic levels and so was substituted with carbamazepine. Chemotherapy caused carbamazepine levels to drop below therapeutic levels resulting in seizures. Increasing the dose from 30 to 50 mg/kg per day prevented subtherapeutic levels. 8
Phenytoin Methotrexate Mercaptopurine Vincristine Acute lymphoblastic leukaemia Phenytoin levels dropped from 19.8 micrograms/mL on the day before chemotherapy to 3.6 micrograms/mL on the 6th day of chemotherapy. 9
Phenytoin Cisplatin Carmustine Etoposide CNS tumours Dose of phenytoin had to be increased by 50 to 300 % in 10 patients to maintain phenytoin levels in the therapeutic range. 10
Sodium valproate Methotrexate (high dose) Acute lymphoblastic leukaemia A child had a seizure a few hrs after methotrexate. Serum valproate levels reduced by 75%. The valproate dose was increased by 50 % and clonazepam added. 11
Sodium valproate Methotrexate Cytarabine Nimustine (by CSF perfusion) Glioblastoma CSF valproic acid levels reduced by 70 % during the perfusion, but returned to normal levels within 7 hours. 12
Sodium valproate Phenytoin Cisplatin Etoposide Bleomycin Testicular cancer Serum valproate levels reduced by 50 % after the first cycle and generalised tonic-clonic seizures occurred. There was no effect on phenytoin levels. 13

Antiepileptics - Drug Interactions

The antiepileptic drugs find their major application in treatment of various kinds of epilepsy, although some of them are also used for other conditions, such as pain management.

The drugs used as antiepileptics are a disparate group,and their interactions need to be considered individually. Carbamazepine and phenytoin have established ranges of therapeutic plasma levels and these are typically fairly narrow. Modest changes in plasma levels may therefore be clinically important.

Carbamazepine is extensively metabolised by cytochrome P450 isoenzyme CYP3A4 to active metabolite, carbamazepine-10,11-epoxide, which is then further metabolised. Concurrent use of CYP3A4 inhibitors or inducers may therefore lead to toxicity or reduced efficacy. However,importantly, carbamazepine also induces CYP3A4 and so induces its own metabolism (autoinduction). Because of this,it is important that drug interaction studies are multiple-dose and carried out at steady state. Auto-induction also means that moderate inducers of CYP3A4 may have less of an effect on steady-state carbamazepine levels than expected. Oxcarbazepine is a derivative of carbamazepine,but has a lesser effect on CYP3A4. However,both carbamazepine and oxcarbazepine can act as inhibitors of CYP2C19, see Phenytoin + Carbamazepine interaction.

Phenobarbital is an inducer of a wide range of cytochrome P450 isoenzymes, and may increase metabolism of a variety of drugs. It may,itself, also be affected by some enzyme inducers or inhibitors, although these interactions are less established.

Phenytoin is extensively metabolised by hydroxylation,principally by CYP2C9, although CYP2C19 also plays a role. These isoenzymes show genetic polymorphism’,, and CYP2C19 may assume a greater role in individuals who have a poor metaboliser phenotype of CYP2C9. The concurrent use of inhibitors of CYP2C9,and sometimes also CYP2C19, can lead to phenytoin toxicity. In addition,phenytoin metabolism is saturable (it shows non-linear pharmacokinetics), and therefore small changes in metabolism or phenytoin dose can result in marked changes in plasma levels. Moreover,phenytoin is highly protein bound, and drugs that alter its protein binding may alter its levels. Although protein binding interactions are usually not clinically relevant (unless metabolism is also inhibited,see ‘Phenytoin + Valproate), they can be important in interpreting drug levels.

Valproate is a generic name that is applied in this section to cover valproic acid and its salts and esters. Valproate undergoes glucuronidation and :7.8pt; font-weight:normal; color:#000000″>βoxidation,and possibly also some metabolism via CYP2C isoenzymes. It can therefore undergo drug interactions via a variety of mechanisms. It acts as an inhibitor of glucuronidation and so may affect other drugs that undergo glucuronidation. Valproate also has non-linear pharmacokinetics due to saturation of plasma protein binding,and so may interact with drugs that alter its protein binding. However,note that, although protein binding interactions are usually not clinically relevant unless metabolism is also inhibited, they can be important in interpreting drug levels.

Of newer antiepileptics, both felbamate and topiramate are weak inducers of CYP3A4. They may also inhibit CYP2C19. They are also partially metabolised by cytochrome P450 isoenzyme system, so may have their metabolism altered by other drugs such as older enzyme-inducing antiepileptics.

Gabapentin, lamotrigine, levetiracetam, tiagabine, vigabatrin, and zonisamide do not appear to act as inhibitors or inducers of cytochrome P450 isoenzymes, and so appear to cause less drug interactions than older antiepileptics. Moreover, gabapentin, levetiracetam, and vigabatrin do not appear to be metabolised by cytochrome P450 system, so appear to be little affected by drug interactions that result from this mechanism. Tiagabine and zonisamide are metabolised by cytochrome P450 system, so may have their metabolism altered by other drugs such as older enzyme-inducing antiepileptics. Lamotrigine is metabolised by glucuronidation,and may be affected by inhibitors (e.g. valproate) or inducers (e.g. the older enzyme-inducing antiepileptics) of this process. Lamotrigine may also act as an inducer of glucuronidation.

Sulphonylureas; Tolbutamide + Tolcapone - Drug Interactions

Clinical evidence,mechanism, importance and management

In a single-dose study in 12 healthy subjects, tolcapone 200mg had no effect on pharmacokinetics of tolbutamide 500 mg, and did not alter glucose-lowering effect of tolbutamide (See reference number 1). This study was conducted since in vitro evidence showed that tolcapone inhibits cytochrome P450 isoenzyme CYP2C9, by which tolbutamide is metabolised. However, findings in healthy subjects suggest that no clinically relevant changes in pharmacokinetics of tolbutamide are likely.

1. Jorga KM,Fotteler B, Gasser R, Banken L, Birnboeck H. Lack of interaction between tolcapone and tolbutamide in healthy volunteers. J Clin Pharmacol (2000) 40, 544–51.

Pioglitazone + Fexofenadine - Drug Interactions

A study in healthy subjects indicated that pharmacokineticsof pioglitazone 45mg daily are not significantly affected by fexofenadine 60mg twice daily, and that pioglitazone does not affectthe pharmacokinetics of fexofenadine.(See reference number 1)

1. Robert M. Pharmacokinetics of coadministration of pioglitazone with fexofenadine. Diabetes (2001) 50 (Suppl 2),A443.

Sulphonylureas + Chloramphenicol Reporting (1987) 24, 24. - Drug Interactions

Studies in diabetics have shown that chloramphenicol 2 g daily can increase serum level and half-life of tolbutamide twofold, and two to threefold, respectively (See reference number 1,2). Blood glucose levels were reduced by about 25 to 30 % (See reference number 2,3). Hypoglycaemia,acute in one case, developed in two other patients taking tolbutamide with chloramphenicol (See reference number 4,5). In another study chloramphenicol 1 to 2 g daily caused an average twofold increase in half-life of chlorpropamide (See reference number 6).

Chloramphenicol inhibits liver enzymes concerned with metabolism of tolbutamide, and probably chlorpropamide as well, leading to their accumulation in body. This is reflected in prolonged half-lives,reduced blood glucose levels and occasionally acute hypoglycaemia (See reference number 1-4,6).

The interaction between tolbutamide and chloramphenicol is well established and of clinical importance. The incidence is uncertain,but increased blood glucose-lowering effects should be expected if both drugs are given. The interaction between chlorpropamide and chloramphenicol is less well documented. Nevertheless, monitor concurrent use carefully and reduce dosage of sulphonylureas as necessary. Some patients may show a particularly exaggerated response. The manufacturers of other sulphonylureas often list chloramphenicol as an interacting drug,based on its interactions with tolbutamide and chlorpropamide, but direct information of an interaction does not appear to be available. No interaction would be expected with chloramphenicol eye drops, because systemic absorption is likely to be small.

Christensen LK,Skovsted L. Inhibition of drug metabolism by chloramphenicol. Lancet (1969) ii, 1397–9.

Brunová E,Slabochová Z, Platilová H, Pavlík F, Grafnetterová J, Dvoráček K. Interaction of tolbutamide and chloramphenicol in diabetic patients. Int J Clin Pharmacol Biopharm (1977) 15, 7–12.

Brunová E,Slabochová Z, Platilová H. Influencing the effect of Dirastan (tolbutamide). Simultaneous administration of chloramphenicol in patients with diabetes and bacterial urinary tractinflammation. Cas Lek Cesk (1974) 113, 72–5.

Ziegelasch H-J. Extreme hypoglykämie unter kombinierter behandlung mit tolbutamid,n-1butylbiguanidhydrochlorid und chloramphenikol. Z Gesamte Inn Med (1972) 27, 63–6.

Soeldner JS,Steinke J. Hypoglycemia in tolbutamide-treated diabetes. JAMA (1965) 193, 398–

9.

6. Petitpierre B,Perrin L, Rudhardt M, Herrera A, Fabre J. Behaviour of chlorpropamide in renalinsufficiency and under the effect of associated drug therapy. Int J Clin Pharmacol (1972) 6, 120–4.

Antidiabetics + Disopyramide - Drug Interactions

Disopyramide occasionally causes hypoglycaemia,which may besevere. Isolated reports describe severe hypoglycaemia when disopyramide was given to diabetic patients taking gliclazide,ormetformin and/or insulin.

Clinical evidence,mechanism, importance and management

Disopyramide occasionally and unpredictably causes hypoglycaemia,which may be severe (See reference number 1-7). The reasons are not fully understood, but in vitro studies suggest that disopyramide and its main metabolite may enhance insulin release from pancreas (See reference number 8). There is a report of severe hypoglycaemia in an 82-year-old woman with diabetes who was taking gliclazide,

which occurred 6 months after she started disopyramide 300mg daily (See reference number 9). A further case of hypoglycaemia associated with disopyramide occurred in a 70-year-old woman who had been taking metformin 500mg twice daily and insulin 62 units daily. Within 3 months of starting disopyramide 250mg twice daily her insulin dose was reduced to 24 units daily,she stopped taking metformin and was eating substantial snacks to avoid hypoglycaemia (See reference number 10). The insulin requirements of another patient with type 2 diabetes were markedly reduced when disopyramide was started (See reference number 11).

The manufacturers note that patients at particular risk for hypoglycaemia are elderly, malnourished, and diabetics, and that impaired renal function and impaired cardiac function may be predisposing factors (See reference number 12,13). They advise close monitoring of blood glucose levels(See reference number 12,13) and withdrawal of disopyramide if problems arise (See reference number 12). This is not simply a problem for diabetics, but certainly within context of diabetes blood glucose-lowering effects of disopyramide may possibly cause particular difficulties. Although not strictly an interaction, concurrent use of disopyramide and antidiabetics should be well monitored because of potential for severe hypoglycaemia, as cases show.

Goldberg IJ,Brown LK, Rayfield EJ. Disopyramide (Norpace)-induced hypoglycemia. Am J Med (1980) 69, 463–6.

Quevdeo SF,Krauss DS, Chazan JA, Crisafulli FS, Kahn CB. Fasting hypoglycemia secondary to disopyramide therapy. Report of two cases. JAMA (1981) 245, 2424.

Strathman I,Schubert EN, Cohen A, Nitzberg DM. Hypoglycemia in patients receiving disopyramide phosphate. Drug Intell Clin Pharm (1983) 17, 635–8.

Semel JD,Wortham E, Karl DM. Fasting hypoglycemia associated with disopyramide. Am Heart J (1983) 106, 1160–1.

Seriès C. Hypoglycémie induite ou favorisée par le disopyramide. Rev Med Interne (1988) 9,528–9.

Cacoub P,Deray G, Baumelou A, Grimaldi C, Soubrie C, Jacobs C. Disopyramide-inducedhypoglycemia: case report and review of the literature. Fundam Clin Pharmacol (1989) 3, 527–35.

Stapleton JT,Gillman MW. Hypoglycemic coma due to disopyramide toxicity. South Med J (1983) 76, 1453.

Horie M,Mizuno N, Tsuji K, Haruna T, Ninomiya T, Ishida H, Seino Y, Sasayama S. Disopyramide and its metabolite enhance insulin release from clonal pancreatic :5.5pt; font-weight:normal; color:#000000″>β-cells by blocking KATP channels. Cardiovasc Drugs Ther (2001) 15, 31–9.

Wahl D,de Korwin JD, Paille F, Trechot P, Schmitt J. Hypoglycémie sévère probablementinduite par le disopyramide chez un diabétique. Therapie (1988) 43, 321–2.

Reynolds RM,Walker JD. Hypoglycaemia induced by disopyramide in a patient with type 2diabetes mellitus. Diabet Med (2001) 18, 1009–10.

Onoda N,Kawagoe M, Shimizu M, Komori T, Takahashi C, Oomori Y, Hirata Y. A case ofnon-insulin dependent diabetes mellitus whose insulin requirement was markedly reduced after disopyramide treatment for arrhythmia. Nippon Naika Gakkai Zasshi (1989) 78, 820–5.

Rythmodan Capsules (Disopyramide). Sanofi-Aventis. UK Summary of product characteristics,November 2005.

Norpace (Disopyramide). Pharmacia. US Prescribing information,September 2001.

Antidiabetics + Clonidine - Drug Interactions

There is evidence that clonidine may possibly suppress signsand symptoms of hypoglycaemia in diabetic patients. Marked hyperglycaemia occurred in a child using insulin when clonidinewas given. However, effect of clonidine on carbohydrate metabolism appears to be variable, as other reports have describedboth increases and decreases in blood glucose levels. Clonidinepremedication may decrease or increase hyperglycaemic response to surgery.

Clinical evidence,mechanism, importance and management

Studies in healthy subjects and patients with hypertension found that their normal response to hypoglycaemia (tachycardia,palpitations, perspiration) caused by a 0.1 unit/kg dose of insulin was markedly reduced when they were taking clonidine 450 to 900 micrograms daily (See reference number 1,2). In contrast,a study in healthy subjects and non-diabetic patients found that clonidine raises blood glucose levels, apparently by reducing insulin secretion,(See reference number 3) and hypoglycaemia was associated with clonidine testing for growth hormone deficiency in 4 children (See reference number 4).

A 9-year-old girl with type 1 diabetes stabilised with insulin 4 units daily,developed substantial hyperglycaemia and needed up to 56 units of insulin daily when she began to take clonidine 50 micrograms daily for Tourette’s syndrome. When clonidine was stopped, she had numerous hypoglycaemic episodes, and within a few days it was possible to reduce her daily dosage of insulin to 6 units (See reference number 5). A patient with type 2 diabetes and hypertension experienced elevated blood glucose levels and decreased insulin secretion when clonidine was given (See reference number 6). However, a study in 10 diabetic patients with hypertension found that although clonidine impaired response to an acute glucose challenge, it did not significantly affect diabetic control over a 10-week period (See reference number 7).

In contrast,a placebo-controlled, crossover study in 20 patients with type 2 diabetes found that transdermal clonidine significantly reduced mean fasting plasma glucose levels by 9 % (See reference number 8).

Forty patients with type 2 diabetes (controlled by diet alone,sulphonylureas, biguanides, or insulin), having eye surgery under general anaesthesia, were given either clonidine 225 to 375 micrograms or flunitrazepam as premedication. In diabetic patients there is an increase in blood glucose during stress because of an increase in catecholamine release. Therefore patients were also given a continuous infusion of insulin to maintain blood glucose at 5.5 to 11.1 mmol/L. Clonidine decreased insulin requirement because of improved blood glucose control due to inhibition of catecholamine release (See reference number 9). Contrasting results were found in a study in 16 non-diabetic women undergoing abdominal hysterectomy. Eight were given intravenous clonidine 1 microgram/kg and 8 control patients were given saline. Intraoperative plasma glucose levels were higher in clonidine group and these patients also had lower insulin levels (See reference number 10).

The suggested reason for a reduced response to hypoglycaemia is that clonidine depresses output of catecholamines (adrenaline, noradrenaline), which are secreted in an effort to raise blood glucose levels, and which are also responsible for these signs (See reference number 2). It seems possible that clonidine will similarly suppress signs and symptoms of hypoglycaemia that can occur in diabetics, but there seem to be no reports confirming this.

The effect of clonidine on carbohydrate metabolism in diabetic patients appears to be variable and general importance of these interactions is uncertain. In diabetic patients there is an increase in blood glucose during stress because of an increase in catecholamine release. The influence of clonidine on surgical stress response appears to vary depending on dose of clonidine and type of surgery.(See reference number 10)Thus, clonidine at about 4 micrograms/kg may attenuate hyperglycaemic response to neurosurgical and non-abdominal procedures, but low-dose clonidine accentuates hyperglycaemic response to lower abdominal surgery, which results from a decrease in plasma insulin.(See reference number 9,10)

Hedeland H,Dymling J-F, Hökfelt B. The effect of insulin induced hypoglycaemia on plasmarenin activity and urinary catecholamines before and following clonidine (Catapresan) in man. Acta Endocrinol (Copenh) (1972) 71, 321–30.

Hedeland H,Dymling J-F, Hökfelt B. Pharmacological inhibition of adrenaline secretion following insulin induced hypoglycaemia in man: the effect of Catapresan. Acta Endocrinol (Copenh) (1971) 67, 97–103.

Metz SA,Halter JB, Robertson RP. Induction of defective insulin secretion and impaired glucose tolerance by clonidine. Selective stimulation of metabolic alpha-adrenergic pathways.Diabetes (1978) 27, 554–62.

Huang C,Banerjee K, Sochett E, Perlman K, Wherrett D, Daneman D. Hypoglycemia associated with clonidine testing for growth hormone deficiency. J Pediatr (2001) 139, 323–4.

Mimouni-Bloch A,Mimouni M. Clonidine-induced hyperglycemia in a young diabetic girl.Ann Pharmacother (1993) 27, 980.

Okada S,Miyai Y, Sato K, Masaki Y, Higuchi T, Ogino Y, Ota Z. Effect of clonidine on insulin secretion: a case report. J Int Med Res (1986) 14, 299–302.

Guthrie GP,Miller RE, Kotchen TA, Koenig SH. Clonidine in patients with diabetes and mildhypertension. Clin Pharmacol Ther (1983) 34, 713–17.

Giugliano D,Acampora R, Marfella R, La Marca C, Marfella M, Nappo F, D’Onofrio F. Hemodynamic and metabolic effects of transdermal clonidine in patients with hypertension andnon-insulin-dependent diabetes mellitus. Am J Hypertens (1998) 11, 184–9.

Belhoula M,Ciébiéra JP, De La Chapelle A, Boisseau N, Coeurveille D, Raucoules-Aimé M.Clonidine premedication improves metabolic control in type 2 diabetic patients during ophthalmic surgery. Br J Anaesth (2003) 90, 434–9.

Lattermann R,Schricker T, Georgieff M, Schreiber M. Low dose clonidine premedication accentuates the hyperglycemic response to surgery. Can J Anesth (2001) 48, 755–9.

Antidiabetics + Allopurinol - Drug Interactions

Allopurinol adversely affected glycaemic control in a patient withtype 2 diabetes receiving insulin. Allopurinol caused an increasein half-life of chlorpropamide, and a minor decrease in thehalf-life of tolbutamide, but effect of these changes on hypoglycaemic response of patients is uncertain. Marked hypoglycaemia and coma occurred in one patient taking gliclazide andallopurinol.

A case report describes improved glycaemic control in a type 2 diabetic patient after allopurinol was stopped. Despite restricted food intake and an increasing dose of insulin, his glycaemic control was poor (fasting blood glucose 14.8 mmol/L) when he took allopurinol 100mg twice daily. However, within a few days of stopping allopurinol, an unexpected improvement in glycaemic control was observed (fasting blood glucose reduced to less than 11 mmol/L). He was later rechallenged with allopurinol,which resulted in reduced glucose tolerance, but increased insulin response, suggesting increased insulin resistance. Hyperuricaemia was later controlled with probenecid, which did not adversely affect glycaemic control (See reference number 1).

A brief report describes 6 patients taking chlorpropamide with allopurinol. The half-life of chlorpropamide in one patient with gout and normal renal function exceeded 200 hrs (normally 36 hours) after allopurinol had been taken for 10 days, and in 2 others half-life was extended to 44 and 55 hours. The other 3 patients were given allopurinol for only 1 or 2 days and half-life of chlorpropamide remained unaltered (See reference number 2).

Severe hypoglycaemia (1.6 mmol/L) and coma occurred in a patient with renal impairment taking gliclazide and allopurinol (See reference number 3). Hypoglycaemia has been seen in another patient taking both drugs,but an interaction is less clear, as enalapril and ranitidine, which may also (rarely) interact were also involved (See reference number 3).

Allopurinol 2.5 mg/kg twice daily for 15 days reduced half-life of intravenous tolbutamide in 10 healthy subjects by 25%, from 360 to 267 minutes (See reference number 4,5).

In case of chlorpropamide it has been suggested that it possibly involves some competition for renal tubular mechanisms (See reference number 2)

Information is very limited. Only gliclazide has been implicated in severe hypoglycaemia with allopurinol and there seem to be no reports of either grossly enhanced hypoglycaemia with chlorpropamide and allopurinol,or a reduced effect with tolbutamide and allopurinol. More study is needed to find out whether any of these interactions has general clinical importance,but it seems unlikely.

Ohashi K,Ishibashi S, Yazaki Y, Yamada N. Improved glycemic control in a diabetic patientafter discontinuation of allopurinol administration. Diabetes Care (1998) 21, 192–3.

Petitpierre B,Perrin L, Rudhardt M, Herrera A, Fabre J. Behaviour of chlorpropamide in renalinsufficiency and under the effect of associated drug therapy. Int J Clin Pharmacol (1972) 6, 120–4.

Girardin E,Vial T, Pham E, Evreux J-C. Hypoglycémies induites par les sulfamides hypoglycémiants. Ann Med Interne (Paris) (1992) 143, 11–17.

Gentile S,Porcellini M, Loguercio C, Foglia F, Coltorti M. Modificazioni della depurazioneplasmatica di tolbutamide e rifamicina-SV indotte dal trattamento con allopurinolo in volontari sono. Progr Med (Napoli) (1979) 35, 637–42.

Gentile S,Porcellini M, Foglia F, Loguercio C, Coltorti M. Influenza di allopurinolo sull’emivita plasmatica di tolbutamide e rifamicina-SV in soggetti sani. Boll Soc Ital Biol Sper (1979) 55, 345–8.

Antidiabetics - Drug Interactions

The antidiabetics are used to control diabetes mellitus, a disease in which there is total or partial failure of beta-cells within pancreas to secrete enough insulin, one of hormones concerned with handling of glucose. In some cases there is evidence to show that disease results from presence of factors that oppose activity of insulin.

With insufficient insulin, body tissues are unable to take up and utilise glucose that is in circulation in blood. Because of this, glucose, which is derived largely from digestion of food, and which would normally be removed and stored in tissues throughout body, accumulates and boosts glucose in blood to such grossly elevated proportions that kidney is unable to cope with such a load and glucose appears in urine. Raised blood glucose levels (hyperglycaemia) with glucose and ketone bodies in urine (glycosuria and ketonuria) are among manifestations of a serious disturbance in metabolic chemistry of body, which, if untreated, can lead to development of diabetic coma and death.

There are two main types of diabetes: one develops early in life and occurs when ability of pancreas suddenly, and often almost totally, fails to produce insulin. This type is called type 1,juvenile, or insulin-dependent diabetes (IDDM), and requires insulin replacement therapy. The other form is type 2,maturity-onset, or non-insulin dependent diabetes mellitus (NIDDM), which is most often seen in those over 40 years old. This occurs when pancreas gradually loses ability to produce insulin over a period of months or years and/or resistance to action of insulin develops. It is often associated with being overweight and can sometimes be satisfactorily controlled simply by losing weight and adhering to an appropriate diet. This may then be augmented with oral antidiabetic drugs,and eventually insulin. A classification of antidiabetics is given in table 1 below,.

Modes of action of antidiabetics

Pramlintide is a synthetic analogue of amylin,a pancreatic hormone involved in glucose homoeostasis. It slows rate of gastric emptying and reduces appetite. It is given subcutaneously immediately prior to meals,and is used in patients already receiving insulin.

Exenatide is an incretin mimetic that acts as a glucagon-like peptide-1 (GLP-1) receptor agonist. This increases insulin secretion when glucose levels are high. It is given subcutaneously as an adjunct in type 2 diabetes in patients already receiving metformin,a sulphonylurea, or both.

Insulin extracted from pancreatic tissue of pigs and cattle is so similar to human insulin that it can be used as a replacement. However,human insulin, manufactured by genetically engineered microorganisms, is more commonly used. Insulin is usually given by injection in order to bypass enzymes of gut, which would digest and destroy it like any other protein. The onset and duration of action of insulin may be prolonged by complexing with zinc or protamine. More recently,various insulin analogues have been developed, which have specific pharmacokinetic profiles. Insulin aspart and lispro have a faster onset and shorter duration of action than soluble insulin. Insulin glargine and detemir both have a prolonged duration of action.

Epalrestat inhibits enzyme aldose reductase, which converts glucose to sorbitol. The accumulation of sorbitol may play a role in some diabetic complications.

Acarbose, miglitol and voglibose act against alpha glucosidases and specifically against sucrase in gut to delay digestion and absorption of monosaccharides from starch and sucrose.

The mode of action of biguanides, such as metformin, is obscure, but they do not stimulate pancreas like sulphonylureas to release insulin, but appear to facilitate uptake and utilisation of glucose by cells in some way. Their use is restricted to type 2 diabetes because they are not effective unless insulin is present.

The meglitinides (e.g. repaglinide) increase endogenous insulin secretion,and so are used in type 2 diabetes.

The sulphonylurea and other sulfonamide-related compounds such as chlorpropamide and tolbutamide were first synthetic compounds used in medicine as antidiabetics. Among their actions they stimulate remaining beta-cells of pancreas to grow and secrete insulin which, with a restricted diet, controls blood glucose levels and permits normal metabolism to occur. Clearly they can only be effective in those diabetics whose pancreas still has capacity to produce some insulin, so their use is confined to type 2 diabetes.

Outside orthodox Western medicine,there are herbal preparations which are used to treat diabetes and which can be given by mouth. Blueberries were traditionally used by Alpine peasants, and bitter gourd or karela (Momordica charantia) is an established part of herbal treatment in Indian subcontinent and elsewhere. Traditional Chinese medicine also has herbal medicines for diabetes. As yet it is not known how these herbal medicines act and their efficacy awaits formal clinical evaluation.

The commonest interactions with antidiabetic drugs are those that result in a rise or fall in blood glucose levels, thereby disturbing control of diabetes. These are detailed in this section. Other interactions where anti-diabetic drug is affecting drug are described elsewhere.

1 Drugs used in management of diabetes

Insulin zinc suspension,Isophane insulin, Protamine zinc insulin

Insulin aspart,Insulin glulisine, Insulin lispro

Insulin aspart protamine,Insulin detemir, Insulin glargine, Insulin lispro protamine

Acarbose,Miglitol, Voglibose

Buformin,Metformin, Phenformin

Nateglinide,Repaglinide

Acetohexamide,Carbutamide, Chlorpropamide, Glibenclamide (Glyburide), Glibornuride, Gliclazide, Glimepiride, Glipizide, Gliquidone, Glisentide, Glisolamide, Glisoxepide, Glycyclamide, Tolazamide, Tolbutamide

Pioglitazone,Rosiglitazone

Table 1 Drugs used in the management of diabetes
Group Drugs
Parenteral antidiabetics
Amylin analogues Pramlintide
Incretin mimetics (Glucagon like peptide-1 (GLP-1) receptor agonist) Exenatide
Insulins Short-acting Soluble insulin
Intermediate- and long-acting Insulin zinc suspension, Isophane insulin, Protamine zinc insulin
Short-acting analogues Insulin aspart, Insulin glulisine, Insulin lispro
Intermediate to long-acting analogues Insulin aspart protamine, Insulin detemir, Insulin glargine, Insulin lispro protamine
Oral antidiabetics
Aldose reductase inhibitors Epalrestat
Alpha glucosidase inhibitors Acarbose, Miglitol, Voglibose
Biguanides Buformin, Metformin, Phenformin
Meglitinides Nateglinide, Repaglinide
Sulphonylureas Acetohexamide, Carbutamide, Chlorpropamide, Glibenclamide (Glyburide), Glibornuride, Gliclazide, Glimepiride, Glipizide, Gliquidone, Glisentide, Glisolamide, Glisoxepide, Glycyclamide, Tolazamide, Tolbutamide
Thiazolidinediones (Gamma-PPAR (peroxisome proliferator-activated receptor) agonists) Pioglitazone, Rosiglitazone
Other drugs Guar gum

Heparin + Aprotinin - Drug Interactions

The activated clotting time (ACT) may not be a reliable methodto monitor heparin therapy when aprotinin is used concurrently.This is because aprotinin increases ACT monitored by somemethods, without actually increasing anticoagulation.

Clinical evidence,mechanism, importance and management

Aprotinin prolongs activated clotting time (ACT) as measured by a celite surface activation method, although kaolin ACT is much less affected (See reference number 1). Therefore, if ACT is used to monitor effectiveness of heparin anticoagulation during cardiopulmonary bypass incorporating aprotinin, this may lead to an overestimation of degree of anticoagulation. This may result in patients not receiving additional necessary heparin during extended extracorporeal circulation, or receiving excess protamine to reverse effects of heparin at end of procedure. The UK manufacturer of aprotinin notes that it is not necessary to adjust usual heparin/protamine regimen used in cardiopulmonary bypass procedures when aprotinin is also used (See reference number 2). The US manufacturer provides additional detailed information on appropriate methods to monitor heparin anticoagulation in presence of aprotinin (See reference number 1).

Trasylol (Aprotinin). Bayer HealthCare. US Prescribing information,December 2003.

Trasylol (Aprotinin). Bayer plc. UK Summary of product characteristics,September 2006.