**2.2. Side effects and drug interactions**

Chronic immunosuppressive therapy has its adverse effects such as lowered seizure threshold, diabetes, hypertension, hyperlipoproteinemia, decreased glomerular filtration, hyperkalemia, hypomagnesemia, increased risk of infection and tumors, pancytopenia, osteoporosis, and poor wound healing. This may have some impact on perioperative management and choice of anesthetic agents (**Table 2**) [10].

The blood level of both cyclosporine and tacrolimus must be kept within the indicated therapeutic range to get the desired effect. The perioperative fluctuation of the plasma level of these two drugs should be strictly monitored. There is a significant reduction of drug blood level by dilution with volume infusion or cardiopulmonary bypass in cardiac surgery [11]. Both these drugs are metabolized by cytochrome P-450 system of liver, and therefore many of the drugs administered perioperatively can affect their plasma levels [12, 13]. A better understanding of


ATG = anti-thymocyte globulin; Aza = azathioprine; CyA = cyclosporine A; MMF = mycophenolate mofetil; OKT3 = monoclonal antibodies directed against CD-3 antigen on the surface of human T-lymphocytes; Ster = steroids; and Tac = tacrolimus.

**Table 2.** Side effects of immunosuppressive that have direct impact on anesthetic and perioperative management [1].

pharmacokinetics over the years, allows now days a reduction of immunosuppressant dose in elderly patients while maintaining the therapeutic level [14].

In the hospital settings, almost 3–5% of adverse drug reactions are due to drug-drug interactions. It is estimated that the percentage is even higher in solid organ transplant recipients dependent on immunosuppressive therapy. Reactions can be among two immunosuppressants or between the immunosuppressant and other drugs [15]. Due to the fact that the administration of cyclosporine (CyA) and tacrolimus (Tac) is ever increasing, we give an overview of their interaction with other drugs (**Table 3**).

During anesthesia, we provide a range of drugs from different groups, which increase the possibility of drug interaction and thus potentially endanger the patient in the perioperative period. One should keep in mind that many pharmacokinetic and pharmacodynamic interactions can occur among the drugs that patients take after transplantation, due to cytochrome P450 enzyme system induction or inhibition by another drug. There are few data concerning interaction between immunosuppressive drugs and anesthetic agents. Most of the evidence is based on clinical practice and occasional case reports or case studies. Large randomized controlled trials involving either general or regional anesthesia are still lacking. **Table 4** describes the effect of various anesthetic agents on immunosuppressant and vice versa.

Cyclosporine and tacrolimus increase blood level of benzodiazepines. Transplanted patients need dose modification [12, 13]. Propofol infusion does not modify the cyclosporine concentration. It is considered to be a suitable agent for intravenous anesthesia in cyclosporine-treated patients, provided a close postoperative monitoring of cyclosporine blood concentrations is maintained [18]. Cyclosporine tends to increase the analgesic effect produced by fentanyl, but

**Drug class Drug Effect on blood level**

flurazepam, clonazepam

norfloxacin, levofloxacin

Antimicrobial Rifampicin ↓ CyA and Tac level Antimalarial Chloroquine, mefloquine ↑ CyA and Tac level

cobicistat, delaviridine

felodipine

pravastatin

Oral hypoglycemics Sulfonylurea, biguanides ↑ CyA level

Analgesics Nonsteroidal anti-inflammatory drugs ↑ CyA and Tac level

trazodone, pimozide

Hormones Estrogen and testosterone preparation ↑ CyA and Tac level Others Bosentan, carbamazepine ↓ CyA and Tac level

ranitidine

voriconazole, amphotericin B

Amiodarone, lidocaine, quinidine, verapamil, diltiazem, amlodipine,

Anticoagulants Apixaban, dabigatran, rivaroxaban ↑ Anticoagulant concentration

lansoprazole, octreotide, cimetidine,

Benzodiazepines Diazepam, midazolam, alprazolam,

Antifungal Ketoconazole, fluconazole, itraconazole,

Anti-retroviral Ritonavir, atazanavir, darunavir,

Statins Simvastatin, atorvastatin, lovastatin,

Gastrointestinal Metoclopramide, omeprazole,

Antipsychotics Haloperidol, desipramine, fluoxetine,

**Table 3.** Drugs that interact with cyclosporine A and tacrolimus.

Cardiovascular drugs

blocker)

(antiarrhythmics and calcium channel

Antibiotics Erythromycin, metronidazole,

**Adverse effect**

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↑ Benzodiazepines

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↑ CyA and Tac level

↑ CyA and Tac level Renal dysfunction

↑ CyA and Tac level

↑ CyA and Tac level

↑ Statin concentration

↑ CyA and Tac level Renal dysfunction

Renal dysfunction

↑ CyA and Tac level ↑ Pimozide level

with Tac

QT prolongation by octreotide

and quinidine

QT prolongation by amiodarone

Most of relaxants can be used safely. Cyclosporine enhances the effects of muscle relaxants. Prolonged neuromuscular block in patients receiving cyclosporine after vecuronium and pancuronium administration has been described [20, 21]. Atracurium and cisatracurium

the mechanism is unclear [19].

CyA = cyclosporine A; Tac = tacrolimus.

Data on the effects of general anesthesia on cyclosporine or tacrolimus pharmacokinetics in humans are limited. Most of the inhalational anesthetic agents are well tolerated unless there is a significant heart failure. However, caution is advised in concurrent administration of oral cyclosporine and isoflurane anesthesia. Subtherapeutic blood levels have been reported in patients who received peroral drug form less than 4 hours preoperatively. It is probably due to a reduction in gastric emptying and absorption from the proximal small bowel, which can occur during isoflurane anesthesia [16]. Steady-state blood levels of cyclosporine and cyclosporine clearance are not altered by isoflurane/nitrous oxide anesthesia in animal model [17].


CyA = cyclosporine A; Tac = tacrolimus.

pharmacokinetics over the years, allows now days a reduction of immunosuppressant dose

**Table 2.** Side effects of immunosuppressive that have direct impact on anesthetic and perioperative management [1].

ATG = anti-thymocyte globulin; Aza = azathioprine; CyA = cyclosporine A; MMF = mycophenolate mofetil; OKT3 = monoclonal antibodies directed against CD-3 antigen on the surface of human T-lymphocytes; Ster = steroids;

**CyA Tac Aza Ster MMF ATG OKT3** Anemia – – + – + – – Leucopenia – – ++ – + + + Thrombocytopenia – – – – + – – Hypertension ++ + – + – – – Diabetes + ++ – ++ – – – Neurotoxicity + + – + – – – Renal insufficiency + ++ – – – – – Anaphylaxis – – – – – + + Fever – – – – – + +

232 Organ Donation and Transplantation - Current Status and Future Challenges

In the hospital settings, almost 3–5% of adverse drug reactions are due to drug-drug interactions. It is estimated that the percentage is even higher in solid organ transplant recipients dependent on immunosuppressive therapy. Reactions can be among two immunosuppressants or between the immunosuppressant and other drugs [15]. Due to the fact that the administration of cyclosporine (CyA) and tacrolimus (Tac) is ever increasing, we give an overview of

During anesthesia, we provide a range of drugs from different groups, which increase the possibility of drug interaction and thus potentially endanger the patient in the perioperative period. One should keep in mind that many pharmacokinetic and pharmacodynamic interactions can occur among the drugs that patients take after transplantation, due to cytochrome P450 enzyme system induction or inhibition by another drug. There are few data concerning interaction between immunosuppressive drugs and anesthetic agents. Most of the evidence is based on clinical practice and occasional case reports or case studies. Large randomized controlled trials involving either general or regional anesthesia are still lacking. **Table 4** describes

Data on the effects of general anesthesia on cyclosporine or tacrolimus pharmacokinetics in humans are limited. Most of the inhalational anesthetic agents are well tolerated unless there is a significant heart failure. However, caution is advised in concurrent administration of oral cyclosporine and isoflurane anesthesia. Subtherapeutic blood levels have been reported in patients who received peroral drug form less than 4 hours preoperatively. It is probably due to a reduction in gastric emptying and absorption from the proximal small bowel, which can occur during isoflurane anesthesia [16]. Steady-state blood levels of cyclosporine and cyclosporine clearance are not altered by isoflurane/nitrous oxide anesthesia in animal model [17].

the effect of various anesthetic agents on immunosuppressant and vice versa.

in elderly patients while maintaining the therapeutic level [14].

their interaction with other drugs (**Table 3**).

and Tac = tacrolimus.

**Table 3.** Drugs that interact with cyclosporine A and tacrolimus.

Cyclosporine and tacrolimus increase blood level of benzodiazepines. Transplanted patients need dose modification [12, 13]. Propofol infusion does not modify the cyclosporine concentration. It is considered to be a suitable agent for intravenous anesthesia in cyclosporine-treated patients, provided a close postoperative monitoring of cyclosporine blood concentrations is maintained [18]. Cyclosporine tends to increase the analgesic effect produced by fentanyl, but the mechanism is unclear [19].

Most of relaxants can be used safely. Cyclosporine enhances the effects of muscle relaxants. Prolonged neuromuscular block in patients receiving cyclosporine after vecuronium and pancuronium administration has been described [20, 21]. Atracurium and cisatracurium


Immunosuppressed patients are at risk of infections that may be bacterial, viral, fungal, or protozoan. Infection is a significant cause of morbidity and mortality after transplantation [28]. Its presence should also always be preoperatively ruled out (by obtaining laboratory, radiologic, and microbiology tests). It is imperative to emphasize that the immunosuppressed patient may not present the typical signs and symptoms of infection (i.e. fever, leukocytosis). Microbiology advice should be strongly sought for prevention as well as strict control of

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Although transplant patients are considered as risk hosts for infection because of their immune status, there is no evidence to suggest different bacteriology of surgical site infections than for the general population. Antimicrobial coverage need not be expanded to include atypical or opportunistic organisms as long as active infection with such an organism is not present or suspected [30]. Prophylaxis with broad spectrum antibiotic should be administered 1 hour

Transplanted patients may also suffer from diabetes, hypertension, epilepsy, renal dysfunction, bone marrow suppression, lymphoproliferative disorders, and adrenal insufficiency as the side effects of chronic immunosuppressive therapy [31]. Hepatobiliary and pancreatic diseases are relatively common after transplantation, as well as the upper gastrointestinal bleeding secondary to peptic ulcer disease. Surgical stress, corticosteroids, and mycophenolate may contribute to gastrointestinal ulcers [32]. So, it is absolutely necessary to provide stress ulcer

The transplant patient population is considered as high-risk group for developing venous thromboembolism (VTE) given the fact that most of these patients have multiple identifiable risk factors [33]. However, the exact risk of developing VTEs in these patients is not clearly defined in the literature, nor there are clear guidelines regarding the appropriate use of thromboprophylaxis in transplant recipients [34]. In our opinion, VTE prophylaxis should

If patient has a β-lactam allergy: vancomycin or clindamycin

Parenteral: cefoxitin or cefotetan, or cefazolin plus metronidazole

If the patient has a β-lactam allergy: vancomycin or clindamycin

If patient has a β-lactam allergy: vancomycin with or without gentamycin,

be tailored to the patient's specific needs in accordance with current guidelines [35].

or clindamycin

Colon surgery Oral: neomycin plus erythromycin base, or neomycin plus metronidazole.

**Operation Recommended antibiotic prophylaxis** Cardiothoracic surgery Cefazolin, cefuroxime, or cefamandole.

Vaginal or abdominal hysterectomy Cefazolin, cefotetan, cefoxitin or cefuroxime

Vascular surgery Cefazolin or cefuroxime.

Hip or knee arthroplasty Cefazolin or cefuroxime.

**Table 5.** Antimicrobial prophylaxis for selected surgical procedures [30].

infection. Any infection should be treated preoperatively [29].

before surgical incision (depending on hospital protocol) (**Table 5**).

prophylaxis for transplanted patients.

**Table 4.** Effect of specific anesthetic agent on immunosuppressive drugs.

are preferred agents because their elimination is not affected by renal or hepatic function. Therefore, patients receiving cyclosporine as immunosuppressive therapy may require a smaller dose of nondepolarizing muscle relaxant and the recovery time may be prolonged [22]. Neostigmine can lead to bradycardia and cardiac arrest in patients with heart transplantation despite the concurrent use of an antimuscarinic agent [23]. Bupivacaine and ropivacaine can be safely used through regional routes without any side effects [24, 25].
