192: Immunosuppresive and Immunomodulatory Drugs Flashcards
1
Q
What are the characteristics of immunosuppressants compared to immunomodulators?
A
Immunosuppressants have a low therapeutic index, significant pharmacokinetic variability, require precise dosing and monitoring, and impair the immune response in a dose-dependent manner. Immunomodulators have a wider therapeutic index, greater safety margin, more predictable pharmacokinetic properties, less variability, and target specific portions of the immune system.
2
Q
What is the pregnancy category for Mycophenolate Mofetil?
A
Mycophenolate Mofetil is classified as Pregnancy Category A.
3
Q
What are the adverse effects associated with Cyclosporine?
A
Adverse effects of Cyclosporine include nephrotoxicity, hypertension, hepatotoxicity, and neurotoxicity. These risks are increased when used in combination with Mycophenolate Mofetil (MMF).
4
Q
What is the clinical significance of the therapeutic monitoring of Mycophenolate Mofetil (MMF)?
A
Therapeutic monitoring of MMF is important because full therapeutic effect is typically seen after 3 months, monitoring plasma drug levels can help avoid toxicity and ensure efficacy, and adjustments may be needed if serum creatinine increases significantly.
5
Q
What is the mechanism of action of Tacrolimus?
A
Tacrolimus works by binding to FK506 and inhibiting NFAT, blocking cell cycle progression from G1 to S phase in T lymphocytes, thus suppressing the immune response.
6
Q
What are the common side effects of Pimecrolimus?
A
Common side effects of Pimecrolimus include mucocutaneous reactions such as aphthous stomatitis, acneiform eruptions, morbilliform eruptions, folliculitis, and pruritus.
7
Q
What are the implications of a low therapeutic index in immunosuppressants?
A
A low therapeutic index indicates a narrow window between therapeutic and toxic ranges, leading to a higher risk of adverse effects and necessitating careful monitoring of drug levels and patient response.
8
Q
How do immunomodulators differ from immunosuppressants in terms of therapeutic index and safety?
A
Immunomodulators have a wider therapeutic index, greater safety margin, and more predictable pharmacokinetic properties compared to immunosuppressants, which have a narrow therapeutic index and significant variability.
9
Q
What is the clinical significance of monitoring plasma drug levels in patients on immunosuppressants?
A
Monitoring plasma drug levels helps to avoid toxicity and ensure therapeutic efficacy by adjusting doses based on individual pharmacokinetics and organ function.
10
Q
What are the potential adverse effects associated with the use of Mycophenolate Mofetil (MMF) when combined with cyclosporine?
A
The combination increases the risk of nephrotoxicity, hepatotoxicity, hypertension, and neurotoxicity, necessitating careful patient management and monitoring.
11
Q
What is the recommended approach to improve tolerability of tacrolimus in patients?
A
Dividing the dose for 3-4 times daily, taking medication with food, and switching to the MP-EC formulation can improve tolerability to tacrolimus.
12
Q
What are the pregnancy categories for Mycophenolate Mofetil, Cyclosporine, and Tacrolimus?
A
Mycophenolate Mofetil is Pregnancy Category A, Cyclosporine is Category B, and Tacrolimus is Category C.
13
Q
What are the clinical implications of reactivation of herpes zoster in patients on immunosuppressive therapy?
A
Reactivation of herpes zoster can lead to significant morbidity in immunosuppressed patients, requiring preventive measures and prompt treatment to manage outbreaks effectively.
14
Q
How does the pharmacokinetic variability affect the dosing of immunosuppressants?
A
Significant intra- and interindividual pharmacokinetic variability necessitates precise drug dosing based on body weight and regular monitoring to avoid toxicity and ensure efficacy.
15
Q
What are the common mucocutaneous side effects associated with Tacrolimus?
A
Common side effects include aphthous stomatitis, acneiform eruptions, morbilliform eruptions, folliculitis, and pruritus.
16
Q
What is the significance of the statement ‘topical tacrolimus and pimecrolimus are contraindicated in Netherton syndrome’?
A
This indicates that these medications can exacerbate the condition, highlighting the importance of understanding specific contraindications in immunosuppressive therapy.
17
Q
What is the expected timeline for the full therapeutic effect of Mycophenolate Mofetil (MMF)?
A
The full therapeutic effect of MMF is typically seen after 3 months of consistent use.
18
Q
What are the clinical implications of flu-like symptoms and headache in patients receiving Everolimus?
A
Flu-like symptoms and headache may indicate an adverse reaction to Everolimus, requiring assessment of the patient’s overall health and potential adjustments in therapy.
19
Q
What is the role of immunosuppressants in managing inflammatory conditions?
A
Immunosuppressants are used to effectively treat inflammatory conditions by inhibiting the immune response, thus reducing inflammation and preventing tissue damage.
20
Q
How does the mechanism of action of Cyclosporine differ from that of Tacrolimus?
A
Cyclosporine binds to cyclophilin and inhibits NFAT, while Tacrolimus binds to FK506 binding protein (FKBP) and inhibits calcineurin, leading to different pathways of immune suppression.
21
Q
What are the implications of poor percutaneous absorption in immunosuppressive drugs?
A
Poor percutaneous absorption can limit the effectiveness of topical immunosuppressive therapies, necessitating alternative routes of administration or formulations.
22
Q
What is the significance of the statement ‘if serum creatinine increases to 10% on 2 consecutive occasions, CsA should be reduced’?
A
This indicates the need for dose adjustment to prevent further renal impairment in patients receiving Cyclosporine A (CsA), highlighting the importance of monitoring renal function.
23
Q
What are the potential side effects of Everolimus in patients undergoing immunosuppressive therapy?
A
Potential side effects include nephrotoxicity, flu-like symptoms, headache, and burning sensation, which require monitoring and management.
24
Q
What is the importance of understanding the pharmacokinetics of immunosuppressive drugs in clinical practice?
A
Understanding pharmacokinetics is crucial for optimizing dosing regimens, minimizing adverse effects, and ensuring therapeutic efficacy in individual patients.
25
What are the implications of significant interindividual variability in the response to immunosuppressive therapy?
Significant interindividual variability necessitates personalized treatment plans and careful monitoring to achieve optimal therapeutic outcomes while minimizing risks.
26
How does the use of immunomodulators potentially reduce the risk of complications related to immune dysfunction?
Immunomodulators may selectively target specific portions of the immune system, thereby reducing the risk of broad immune suppression and associated complications.
27
What are the clinical considerations for managing patients with rosacea on Cyclosporine?
Patients with rosacea may experience exacerbation of their condition when treated with Cyclosporine, requiring careful monitoring and potential adjustments in therapy.
28
What is the significance of the statement 'there is no increased risk of nephrotoxicity when MMF is given with cyclosporine'?
This indicates that the combination of MMF and cyclosporine does not exacerbate nephrotoxic risks, which is important for patient safety and treatment planning.
29
What are the implications of prolonged QT interval in patients receiving Tacrolimus?
Prolonged QT interval can increase the risk of arrhythmias, necessitating monitoring and potential adjustments in therapy to ensure patient safety.
30
What is the role of combination therapy in enhancing the efficacy of immunosuppressive treatment?
Combination therapy can enhance efficacy by allowing for lower doses of individual drugs, reducing toxicity, and improving overall patient outcomes.
31
What are the key considerations for therapeutic monitoring of immunosuppressive drugs?
Key considerations include regular assessment of drug levels, monitoring for adverse effects, and adjusting doses based on individual patient response and organ function.
32
What is the clinical significance of understanding the pharmacodynamics of immunosuppressive agents?
Understanding pharmacodynamics helps clinicians predict therapeutic effects and potential side effects, guiding treatment decisions and patient management.
33
How does the mechanism of action of Pimecrolimus differ from that of other immunosuppressants?
Pimecrolimus primarily acts as a topical agent that inhibits T-cell activation and cytokine release, differing from systemic agents that affect broader immune pathways.
34
What is the mechanism of action of Mycophenolate Mofetil (MMF)?
Mycophenolate Mofetil (MMF) reversibly inhibits the type II isoform of inosine monophosphate dehydrogenase, a key enzyme in the de novo purine synthesis pathway, leading to reduced proliferation of T and B lymphocytes.
35
What are the absolute contraindications for using Mycophenolate Mofetil (MMF)?
The absolute contraindications for Mycophenolate Mofetil (MMF) include hypersensitivity and pregnancy (category D) due to increased risk of pregnancy loss and congenital malformations.
36
What are the common side effects associated with Mycophenolate Mofetil (MMF)?
Common side effects of Mycophenolate Mofetil (MMF) include dose-related gastrointestinal side effects and increased risk of herpes zoster virus reactivation in older patients.
37
What is the recommended dosing regimen for Mycophenolate Mofetil (MMF)?
The recommended dosing regimen for Mycophenolate Mofetil (MMF) is 1 to 1.5g twice daily for adults, with a pediatric dose of 600mg/m².
38
What are the serious adverse effects associated with Mycophenolate Mofetil (MMF)?
Serious adverse effects associated with Mycophenolate Mofetil (MMF) include cytopenias, lymphoma, lymphoproliferative disorder in children, and infections such as JC virus-associated progressive multifocal leukoencephalopathy.
39
A patient on Mycophenolate Mofetil (MMF) develops severe gastrointestinal side effects. What strategies can be employed to improve tolerability?
To improve tolerability of MMF, the total daily dose can be divided into 3-4 doses, taken with food, or switched to the enteric-coated formulation (MP-EC).
40
A patient on Mycophenolate Mofetil (MMF) is planning to conceive. What advice should be given regarding pregnancy?
MMF is contraindicated in pregnancy (Category D) due to risks of pregnancy loss and congenital malformations. Active contraception should be continued for 6-8 weeks after discontinuation of MMF.
41
A patient on Mycophenolate Mofetil (MMF) develops cytopenias. What factors increase the risk of this side effect?
Cytopenias are more common when the maximum dose of MMF is used or when combined with other immunosuppressants.
42
A patient on Mycophenolate Mofetil (MMF) develops a reactivation of herpes zoster. What population is at higher risk for this side effect?
Older patients on MMF are at a higher risk of herpes zoster reactivation.
43
A patient on Mycophenolate Mofetil (MMF) is also taking antacids. What interaction should be considered?
Antacids decrease the absorption of MMF. Administration should be spaced 2 hours before or after MMF.
44
A patient on Mycophenolate Mofetil (MMF) is also taking proton pump inhibitors (PPIs). What interaction should be considered?
PPIs decrease the absorption of MMF. Administration should be spaced 2 hours before or after MMF.
45
A patient on Mycophenolate Mofetil (MMF) is also taking cholestyramine. What interaction should be considered?
Cholestyramine decreases the absorption of MMF. Administration should be spaced appropriately.
46
A patient on Mycophenolate Mofetil (MMF) develops lymphoma. What factors increase the risk of this side effect?
The risk of lymphoma increases when MMF is combined with other immunosuppressants.
47
A patient on Mycophenolate Mofetil (MMF) develops progressive multifocal leukoencephalopathy (PML). What is the causative agent?
PML in MMF users is caused by JC virus infection.
48
A patient on Mycophenolate Mofetil (MMF) develops skin cancer. What factors increase the risk of this side effect?
The risk of skin cancer increases when MMF is combined with other immunosuppressants.
49
What is the recommended dosing regimen for Mycophenolate Mofetil (MMF) in adults?
1 to 1.5g twice daily.
50
What is the pediatric dose of Mycophenolate Mofetil (MMF)?
600mg/m².
51
What should be done for children with BSA >1.5m² when dosing Mycophenolate Mofetil (MMF)?
Use the adult dose.
52
Is Mycophenolate Mofetil (MMF) safe with corticosteroids?
Yes, MMF is safe with corticosteroids.
53
When is the full therapeutic effect of Mycophenolate Mofetil (MMF) typically seen?
After 3 months of treatment.
54
What are common side effects associated with Mycophenolate Mofetil (MMF)?
Dose-related gastrointestinal (GI) side effects.
55
How can tolerability be improved for patients experiencing GI side effects from Mycophenolate Mofetil (MMF)?
1. Further divide the total daily dose into 3-4 times a day.
2. Take medication with food.
3. If side effects persist, consider switching to enteric-coated MMF (MP-EC).
56
What increased risk is associated with Mycophenolate Mofetil (MMF) in older patients?
Increased risk of herpes zoster virus reactivation.
57
What serious adverse effects are associated with Mycophenolate Mofetil (MMF)?
Cytopenias (rare), increased risk of lymphoma and skin cancer, lymphoproliferative disorders in children, infections such as JC virus-associated progressive multifocal leukoencephalopathy.
58
What are the pharmacokinetics of Mycophenolate Mofetil (MMF)?
Absorption is rapid, 97% bound to plasma albumin, metabolized by hepatic glucuronyl transferases to form its inactive glucuronide (MPAG), and excreted almost exclusively in the kidneys.
59
What dosing considerations are there for children taking Mycophenolate Mofetil (MMF)?
Doses required in children may be 20% higher due to increased hepatic metabolism.
60
What is the significance of the enteric-coated formulation of Mycophenolate Mofetil (MP-EC)?
It has fewer gastrointestinal (GI) side effects compared to the standard formulation of MMF.
61
What drug interactions should be considered when administering Mycophenolate Mofetil (MMF)?
Antacids, cholestyramine, and PPIs decrease absorption; space administration of PPIs 2 hours before or after MMF.
62
What is the interaction between Cyclosporine and Mycophenolate Mofetil (MMF)?
Cyclosporine interferes with enterohepatic circulation of MPA, leading to decreased MPA levels.
63
What should be monitored when using Mycophenolate Mofetil (MMF)?
Regular blood counts and serum chemistry; measurement of serum MPA to achieve target trough levels is advocated.
64
What is the effect of Mycophenolate Mofetil (MMF) on immunoglobulin levels?
It leads to decreased immunoglobulin levels due to its mechanism of action.
65
What are the approved indications for Cyclosporine A (CsA)?
Moderate to severe plaque psoriasis, pyoderma gangrenosum, pemphigus, and several other dermatological conditions.
66
What are the contraindications for using Cyclosporine A (CsA)?
Hypersensitivity, severe renal dysfunction, uncontrolled hypertension, malignancy, and phototherapy.
67
What are common side effects associated with Cyclosporine A (CsA)?
Nausea, vomiting, diarrhea, headache, neurological effects, and renal side effects.
68
What is the recommended dosing regimen for Cyclosporine A (CsA)?
2.5 mg/kg/day, can be increased by 0.5 to 1 mg/kg/day at 2-week intervals.
69
What therapeutic monitoring is required for patients on Cyclosporine A (CsA)?
Baseline laboratory studies assessing renal function, electrolytes, and urinalysis; monitoring every 2 weeks initially.
70
What should be done if a patient on Cyclosporine develops hypertension and elevated serum creatinine?
Reduce the CsA dose; if persistently elevated, discontinue CsA.
71
What are the two types of nephrotoxicity associated with Cyclosporine A (CsA)?
1. Acute nephrotoxicity, reversible with dose adjustment. 2. Chronic nephrotoxicity, irreversible, occurring with long-term therapy.
72
What considerations should be taken into account regarding vaccination for patients on Cyclosporine A (CsA)?
Live attenuated vaccines should be avoided due to immunosuppressive effects.
73
What dietary considerations should be noted for patients taking Cyclosporine A (CsA)?
Caution with bioflavonoid-rich foods like grapefruit, which can increase bioavailability.
74
What are potential renal and peripheral vascular effects of immunosuppressive drugs?
Renal vasoconstriction and peripheral vasoconstriction may precipitate Raynaud phenomenon.
75
What lipid and electrolyte abnormalities can occur with immunosuppressive therapy?
Hypercholesterolemia, elevated LDL, hypertriglyceridemia, hypomagnesemia, hyperkalemia or hypokalemia, and hyperuricemia.
76
What musculoskeletal effects can be associated with immunosuppressive drugs?
Osteoporosis and myopathy.
77
What mucocutaneous side effects are associated with immunosuppressive therapy?
Hypertrichosis, gingival hypertrophy, acneiform eruption, keratosis pilaris, sebaceous hyperplasia, warts, and epidermal inclusion cysts.
78
What are some serious adverse effects associated with immunosuppressive drugs?
Significant cytopenia, thrombotic microangiopathy, malignancy, infections, and neurotoxicity.
79
What factors contribute to gingival hypertrophy in patients on Cyclosporine?
More common in children, those with poor oral hygiene, and concomitant use of calcium channel blockers.
80
What is the prognosis for hypertrichosis caused by Cyclosporine?
It has no tendency for spontaneous remission.
81
What is the clinical significance of hyperuricemia in Cyclosporine users?
It may be an early indicator of nephrotoxicity.
82
What is the prognosis for acneiform eruptions caused by Cyclosporine?
The prognosis is variable and may require management.
83
What are the contributing factors for gingival hypertrophy in a patient on Cyclosporine?
Gingival hypertrophy is more common in children, those with poor oral hygiene, and concomitant use of calcium channel blockers like nifedipine.
84
What is the clinical significance of hyperuricemia in Cyclosporine users?
Hyperuricemia in Cyclosporine users may be an early indicator of nephrotoxicity.
85
What is the prognosis for acneiform eruptions caused by Cyclosporine?
Acneiform eruptions caused by Cyclosporine tend to subside with ongoing use.
86
What is the recommended course of action for thrombotic microangiopathy in a patient on Cyclosporine?
Thrombotic microangiopathy is a serious adverse effect of Cyclosporine. The drug should be discontinued, and the patient should receive appropriate supportive care.
87
What are the potential renal effects of immunosuppressive therapy?
- Renal vasoconstriction
- Peripheral vasoconstriction may precipitate Raynaud phenomenon
88
What lipid and electrolyte abnormalities can occur with immunosuppressive drugs?
| Abnormality | Description |
|-------------|-------------|
| Hypercholesterolemia | Elevated cholesterol levels |
| Elevated LDL | Increased low-density lipoprotein levels |
| Hypertriglyceridemia | Elevated triglyceride levels |
| Hypomagnesemia | Low magnesium levels |
| Hyperkalemia or hypokalemia | Altered potassium levels |
| Hyperuricemia | May indicate early nephrotoxicity |
89
What musculoskeletal side effects are associated with immunosuppressive therapy?
- Osteoporosis
- Myopathy
90
What mucocutaneous effects can arise from the use of immunosuppressive drugs?
| Effect | Description |
|--------|-------------|
| Hypertrichosis | No tendency for spontaneous remission |
| Gingival hypertrophy | More common in children, improved with oral metronidazole or azithromycin |
| Acneiform eruption | Skin eruptions resembling acne |
| Disseminated comedonal eruptions | Widespread acneiform lesions |
| Keratosis pilaris | Small, rough bumps on the skin |
| Sebaceous hyperplasia | Enlarged sebaceous glands |
| Warts and epidermal inclusion cysts | Common skin growths |
| Eruptive nevi | New moles appearing rapidly |
91
What are some serious adverse effects associated with immunosuppressive therapy?
| Adverse Effect | Description |
|----------------|-------------|
| Significant cytopenia | Rare occurrence of low blood cell counts |
| Thrombotic microangiopathy | Hemolytic uremic syndrome, especially in bone marrow transplant patients |
| Malignancy | Increased risk of lymphoma and skin cancers |
| EBV-associated disorders | Rare post-transplant lymphoproliferative disorders |
| Melanomas | Reported but incidence is unknown |
| Infections | Associated with JC virus and polyoma virus nephropathy |
| Neurotoxicity | Includes cortical blindness, hemiplegia, and posterior reversible encephalopathy syndrome (PRES) |
92
What is the mechanism of action of Tacrolimus?
Tacrolimus has a mechanism of action similar to Cyclosporine (CsA). It binds to FK506 binding protein instead of cyclophilin, leading to similar downstream effects.
93
What are the indications for topical Tacrolimus?
Topical Tacrolimus is indicated for:
- Atopic dermatitis (approved for ages 2-15 years with moderate to severe cases)
- Off-label uses include seborrheic dermatitis, cutaneous lupus erythematosus, pyoderma gangrenosum, and vitiligo.
94
What are the contraindications for using Tacrolimus?
Tacrolimus is contraindicated in patients with:
- Hypersensitivity
- Active infections
- Malignancy
- Severe hepatic or renal dysfunction
- Netherton syndrome (for topical Tacrolimus).
95
What are the common side effects associated with systemic Tacrolimus?
Common side effects of systemic Tacrolimus include:
- Neurotoxicity
- Glucose intolerance
- Nephrotoxicity characterized by elevated creatinine and hyperkalemia
- Chronic nephrotoxicity which is progressive and irreversible.
96
What therapeutic monitoring is necessary for patients receiving systemic Tacrolimus?
Therapeutic monitoring for systemic Tacrolimus includes:
- Target plasma concentration between 5 and 15 ng/ml
- Regular skin examinations for malignancy
- Monitoring for cutaneous infections during treatment.
97
What precautions should be taken when using topical Tacrolimus to minimize side effects?
To minimize side effects such as stinging and burning from topical Tacrolimus, the following precautions can be taken:
1. Pretreatment with topical steroids
2. Pretreatment with oral aspirin
3. Refrigeration of the product before application.
98
What are the serious adverse effects associated with Tacrolimus?
Serious adverse effects of Tacrolimus include:
- Lymphoma and other malignancies
- Serious infections
- Irreversible nephrotoxicity
- Severe neurotoxicity
- Pure red cell aplasia
- Prolonged QT interval
- GI perforation.
99
What precautions should be taken to minimize side effects of topical Tacrolimus?
To minimize side effects of topical Tacrolimus, apply sparingly to affected areas, avoid occlusion except for short periods, and refrigerate the ointment to reduce stinging and burning. Pretreatment with topical steroids or oral aspirin may also help.
100
What should be done if a patient on Tacrolimus develops prolonged QT interval?
Prolonged QT interval is a serious adverse effect of Tacrolimus. The drug should be discontinued, and the patient should be evaluated for other contributing factors like electrolyte imbalances.
101
What measures can reduce stinging and burning sensations from topical Tacrolimus?
Stinging and burning sensations from topical Tacrolimus can be reduced by pretreatment with topical steroids, oral aspirin, or refrigeration of the ointment.
102
What are the common manifestations of neurotoxicity from Tacrolimus?
Neurotoxicity from Tacrolimus can manifest as cortical blindness, hemiplegia, and posterior reversible encephalopathy syndrome (PRES).
103
What monitoring is recommended for patients on Tacrolimus who develop glucose intolerance?
Patients on Tacrolimus should have regular monitoring of magnesium and glucose levels to detect glucose intolerance.
104
What is the pathophysiology of severe nephrotoxicity from Tacrolimus?
Tacrolimus-induced nephrotoxicity is due to afferent renal vasoconstriction, leading to elevated creatinine, hyperkalemia, and decreased urine output.
105
What are the common manifestations of severe neurotoxicity from Tacrolimus?
Severe neurotoxicity from Tacrolimus can manifest as cortical blindness, hemiplegia, and posterior reversible encephalopathy syndrome (PRES).
106
What is the recommended course of action for pure red cell aplasia in a patient on Tacrolimus?
Pure red cell aplasia is a serious adverse effect of Tacrolimus. The drug should be discontinued, and the patient should receive appropriate supportive care.
107
What populations are at higher risk for severe infections while on Tacrolimus?
Patients with compromised immune systems or those on high doses of Tacrolimus are at higher risk of severe infections.
108
How does Tacrolimus compare to Cyclosporine in terms of mechanism of action?
Tacrolimus has a mechanism of action similar to CsA; it binds to FK506 binding protein instead of cyclophilin, but the downstream effects are similar to those of CsA.
109
What are the approved indications for topical Tacrolimus?
Topical Tacrolimus is approved for use in concentrations of 0.03% and 0.1% for patients aged 2-15 years with moderate to severe atopic dermatitis. It is also used off-label for seborrheic dermatitis, cutaneous lupus erythematosus, pyoderma gangrenosum, and vitiligo.
110
What are the contraindications for using systemic Tacrolimus?
Systemic Tacrolimus is contraindicated in patients with hypersensitivity, active infections, malignancy, severe hepatic or renal dysfunction, and in patients with Netherton syndrome.
111
What therapeutic monitoring is necessary for patients receiving systemic Tacrolimus?
Therapeutic monitoring for systemic Tacrolimus includes targeting plasma concentrations between 5 and 15 ng/ml, evaluating for cutaneous infections during treatment, closely following lymphadenopathy, and performing regular skin examinations for malignancy.
112
What are the potential side effects of systemic Tacrolimus?
Potential side effects of systemic Tacrolimus include neurotoxicity, glucose intolerance, nephrotoxicity characterized by elevated creatinine and hyperkalemia, chronic nephrotoxicity, and mucocutaneous involvement, which is less frequent.
113
What precautions should be taken when applying topical Tacrolimus to minimize side effects?
To minimize side effects such as stinging and burning, it is recommended to: 1. Pretreat with topical steroids, 2. Pretreat with oral aspirin, 3. Refrigerate the medication before application.
114
What are the serious adverse effects associated with Tacrolimus?
Serious adverse effects of Tacrolimus include lymphoma and other malignancies, serious infections, irreversible nephrotoxicity, severe neurotoxicity, pure red cell aplasia, prolonged QT interval, and gastrointestinal perforation.
115
How does Tacrolimus pharmacokinetics differ from that of Cyclosporine (CsA)?
Tacrolimus has better bioavailability, higher potency, and lower molecular weight compared to CsA. It is also less than 1% excreted unchanged in urine and has a longer elimination half-life of 12-21 hours.
116
What is the recommended dosing regimen for topical Tacrolimus?
Topical Tacrolimus should be applied sparingly twice daily and discontinued when signs of skin inflammation have subsided. Once the skin barrier is restored, applications can be reduced to 2-3 times weekly to decrease the need for topical corticosteroids.
117
What considerations should be made regarding drug interactions with Tacrolimus?
Tacrolimus should not be combined with CsA due to overlapping mechanisms of action and toxicity. It does not interfere with enterohepatic circulation, so lower doses of mycophenolate mofetil (MMF) should be used if they are co-prescribed.
118
What is the mechanism of action of Pimecrolimus?
Pimecrolimus binds to FKBP-12 (FK506 binding protein) and has a slightly lower efficacy due to decreased binding to FKBP compared to other calcineurin inhibitors (CNIs).
119
What are the common side effects associated with Everolimus?
Common side effects of Everolimus include mucocutaneous effects such as aphthous stomatitis, acneiform eruption, morbilliform eruption, folliculitis, and pruritus. Other side effects may include diarrhea, fatigue, headache, peripheral edema, and impaired wound healing.
120
What are the contraindications for using Pimecrolimus?
Pimecrolimus is contraindicated in patients with hypersensitivity and Netherton syndrome.
121
What therapeutic monitoring is recommended for Everolimus?
Routine laboratory testing is recommended during Everolimus therapy, with a target plasma concentration between 5 and 15 ng/ml.
122
What is the dosing regimen for Pimecrolimus?
Pimecrolimus is applied twice daily (BID), and continuous long-term use is not recommended.
123
What serious adverse effects are associated with Everolimus?
Serious adverse effects of Everolimus include noninfectious pneumonitis, fatal infections, severe renal and hepatic dysfunction, and capillary leak syndrome during oral sirolimus for psoriasis.
124
What are the indications for using Everolimus?
Everolimus is indicated for hormone receptor-positive breast cancer, neurocrine tumors of pancreatic, GI, or lung origin, advanced renal cell carcinoma, and angiomyolipoma. Off-label uses include psoriasis, atopic dermatitis (AD), Kaposi sarcoma, chronic GVHD, and morphea.
125
What is the typical timeline for mucocutaneous side effects of Everolimus?
Mucocutaneous side effects of Everolimus, such as aphthous stomatitis and acneiform eruptions, typically occur within the first month of therapy.
126
What is the recommended course of action for noninfectious pneumonitis in a patient on Everolimus?
Noninfectious pneumonitis is a serious adverse effect of Everolimus. The drug should be discontinued, and the patient should receive appropriate supportive care.
127
What risks should be considered when co-prescribing Everolimus with Mycophenolate Mofetil (MMF)?
Co-prescription of Everolimus with MMF can increase the risk of cytopenias, hypercholesterolemia, electrolyte disturbances, and elevation of liver enzymes.
128
What is the mechanism behind impaired wound healing in patients on Everolimus?
Everolimus disrupts mTOR kinase activity, which is essential for cell cycle progression and tissue repair, leading to impaired wound healing.
129
What is the underlying mechanism of thrombotic microangiopathy from Everolimus?
Thrombotic microangiopathy from Everolimus is associated with endothelial damage and impaired fibrinolysis.
130
What is the typical timeline for severe diarrhea from Everolimus?
Severe diarrhea from Everolimus typically occurs within the first month of therapy.
131
What is the mechanism behind hypercholesterolemia in patients on Everolimus?
Everolimus disrupts mTOR kinase activity, which can lead to hypercholesterolemia.
132
What is the typical timeline for severe fatigue from Everolimus?
Severe fatigue from Everolimus typically occurs within the first month of therapy.
133
What precautions should be taken for patients on Everolimus to avoid impaired wound healing?
Patients on Everolimus should avoid situations that may require rapid tissue repair, as the drug disrupts mTOR kinase activity essential for wound healing.
134
What is the mechanism of action of Pimecrolimus compared to other calcineurin inhibitors (CNIs)?
Pimecrolimus binds to FKBP-12 (macrophilin-12) to form a complex that inhibits calcineurin, similar to other CNIs. However, it has a slightly lower efficacy due to decreased binding to FKBP compared to other CNIs.
135
What are the primary indications for Everolimus and its off-label uses?
Everolimus is indicated for treating hormone receptor-positive breast cancer, neurocrine tumors of pancreatic, GI, or lung origin, advanced renal cell carcinoma, and angiomyolipoma. Off-label uses include psoriasis, atopic dermatitis (AD), Kaposi sarcoma, chronic GVHD, and morphea.
136
What are the dosing recommendations for Pimecrolimus?
Pimecrolimus should be applied twice daily (BID). Continuous long-term use is not recommended due to potential adverse effects.
137
What are the common side effects associated with Everolimus?
Common side effects of Everolimus include mucocutaneous effects such as aphthous stomatitis, acneiform eruption, morbilliform eruption, folliculitis, and pruritus. Other side effects include diarrhea, fatigue, headache, and peripheral edema.
138
What are the contraindications for using Pimecrolimus?
Pimecrolimus is contraindicated in patients with hypersensitivity to the drug and those with Netherton syndrome. It should also be avoided in patients with premalignant skin conditions and those exposed to phototherapy.
139
How does the pharmacokinetics of Everolimus affect its absorption?
Everolimus has high fat meals that reduce its absorption, with 75% of the drug bound to proteins. It is metabolized in the liver and is a competitive inhibitor of CYP3A4, which can affect drug interactions.
140
What are the contraindications for Pimecrolimus?
Pimecrolimus is contraindicated in patients with hypersensitivity to the drug and those with Netherton syndrome. It should also be avoided in patients with premalignant skin conditions and those exposed to phototherapy.
141
What considerations should be taken into account when prescribing Everolimus with other medications?
When prescribing Everolimus with Mycophenolate Mofetil (MMF) or other calcineurin inhibitors (CNI), caution is advised as it can cause cytopenias, hypercholesterolemia, electrolyte disturbances, and elevation of liver enzymes.
142
What is the recommended therapeutic monitoring for patients on Everolimus?
Routine laboratory testing is recommended for patients on Everolimus, with a target plasma concentration between 5 and 15 ng/ml to ensure safety and efficacy.
143
What are the side effects of Pimecrolimus and how can they be managed?
Side effects of Pimecrolimus include burning and itching, which can be ameliorated by refrigeration. Other effects include acneiform eruptions and cutaneous infections, which may complicate its use. It is generally well tolerated with a wider margin of safety.
144
What is the recommended daily oral dose of Mycophenolate Mofetil for cytotoxic T cell-mediated diseases?
The recommended daily oral dose of Mycophenolate Mofetil for cytotoxic T cell-mediated diseases is 25-55 mg/kg.
145
What are the serious adverse effects associated with Mycophenolate Mofetil?
Serious adverse effects of Mycophenolate Mofetil include:
- Embryotoxicity
- Lymphoma and other malignancies
- Serious and opportunistic infections, including progressive multifocal leukoencephalopathy
- Skin cancer
- Severe cytopenias, including neutropenia and pure red cell aplasia
146
What are the adult dosing regimens for Cyclosporine and Tacrolimus?
| Drug | Adult Dosage (mg/kg/day) |
|---------------|--------------------------|
| Cyclosporine | 2.5-5.0 (oral), 2-3 (IV) |
| Tacrolimus | 0.15-0.20 (oral), 0.025-0.05 (IV) |
147
What are the serious adverse effects of Cyclosporine?
Serious adverse effects of Cyclosporine include:
- Fulminant hepatotoxicity
- Hyperkalemia
- Lymphoma and other malignancies, including skin cancer
- Nephrotoxicity
- Serious and opportunistic infections, including polyoma virus infection (e.g., progressive multifocal leukoencephalopathy)
- Thrombotic microangiopathy/hemolytic uremic syndrome
148
What modifications should be made to Cyclosporine dosing based on serum creatinine levels?
Modifications to Cyclosporine dosing based on serum creatinine levels include:
- Increase 25% above baseline if serum creatinine increases.
- Decrease dose for 1-2 weeks if levels are elevated >25% above baseline.
- Continue current dose if levels are normal or improvement is seen with levels <25% above baseline.
- Discontinue drug if continued elevation >25% above baseline occurs.
149
What drugs are known to interact with Cyclosporine and may increase the risk of nephrotoxicity?
Drugs that may increase the risk of nephrotoxicity when taken with Cyclosporine include:
- Antibiotics: Ciprofloxacin, gentamicin, tobramycin, vancomycin, trimethoprim with sulfamethoxazole
- Antifungals: Amphotericin B, ketoconazole
- Other drugs: Melphalan, methotrexate
150
What are the serious adverse effects of Tacrolimus and Pimecrolimus?
Serious adverse effects include:
- Tacrolimus: Hyperkalemia, lymphoma and other malignancies, nephrotoxicity, neurotoxicity, QT prolongation, serious and opportunistic infections, theoretical risk of lymphoma and skin malignancy.
- Pimecrolimus: Theoretical risk of lymphoma and skin malignancy.
151
What is the pediatric dosing regimen for Tacrolimus intravenous administration?
200-300 µg/kg/day
152
What are the serious adverse effects of Everolimus?
Serious adverse effects of Everolimus include:
- Embryotoxicity
- Hepatotoxicity
- Nephrotoxicity
- Noninfectious pneumonitis
- Serious and opportunistic infections
153
Which drug class can decrease Cyclosporine concentrations?
Antibiotics, such as Nafcillin and Rifampin.
154
What is the theoretical risk associated with Pimecrolimus?
Theoretical risk of lymphoma and skin malignancy.
