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medical school midcomp 5 > Pharmacology Immunosupressant II > Flashcards

Pharmacology Immunosupressant II Flashcards

1
Q

Cyclosporine

A
  • solubilized in ethanol
  • p-glycoprotein & CYP3A4 substrate
  • must monitor plasma concentration
  • attaches to cyclophilin calcineurin inhibitor ..stops IL2
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2
Q

Tacrolimus

A
  • cyp3A4 and p-glycoprotein substrate
  • more potent than cyclosporine
  • calcineurin inhibitor, attaches to FKBP. Stop IL2
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3
Q

Cyclosporine/tacrolimus use

A
  • prophylaxis of solid organ allograft rejection
  • treatment of GVHD after hematopoietic stem cell transplantation
  • inflammatory disease
  • cyclasporine drops for uveitis
  • tacrolimus topically for psoriasis, dermatitis
  • tacrolimus preferred agent because decreased acute rejection rates and better tolerated than cyclosporine
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4
Q

Calcineurin toxicities

A

Nephrotoxicity- vasoconstrictor effect on afferents renal arterial
Interstitial fibrosis
Hypertension
Neurotoxicity- tremor, parenthesis, headache, confusion, seizure
Hyperkalemia
Hyperglycemia
Diarrhea, nausea,vomiting
Hyperuricemia, hyperlipidemia, gum hyperplasia, hirsuitism ( seen with cyclosporine not tacrolimus )

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5
Q

Tacrolimus / cyclosporine Drug interactions

A

CYP3A4/ pglycoprotein inducer and inhibitors
-CYP3A4 inducer. Increases rate of metabolism->dec in serum levels —> inc risk of rejection. Inhibitor are opposite
- pglycoprotein. Inhibitors dec efflux-> inc serum level-> inc toxicity
- drugs that additive toxicity, nephrotoxicity,neurotoxicity
- cyclosporine and tacrolimus not used together
CYP3A4 inducers ( carbamazepine,phenobarbital,phenytoin,rifampin,efavirez,st johns wort)
CYP3A4 inhibitor (verapamil,diltiazim,Azole,macrolide antobiotics,dexmethasone,hiv and hcv protease inhibitors, grapefruit juice

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6
Q

Sirolimus combination adverse effects

A 
Cyclosporine+sacrolimus= administer sacrolimus 4 hrs after csA.sicrolimus aggravates cyclosporine induced renal dysfunction.cyclosporine increase sacrolimus levels. Enhance anemia, leukopenia,thrombocytopenia, hypokalemia,diarrhea
Tacrolimus+sirolimus= avoid combo. Both may enhance each other’s adverse effects.. sicrolimus May dec. tacrolimus concentrations
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7
Q

Mycophenolate mofetil

A
  • anti metabolite, rapidly converted to mycophelonic acid
  • selective, uncompetitive, reversible IMDPH inhibition-> inhibits guanine synthesis->traps cell in G1-S phase->apoptosis
  • decreased lymphocyte function, T cell mediated B cell proliferation and function
  • T and B lymphocytes highly dependent on de novo pathway for cell proliferation
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8
Q

Mycophenolate mofetic therapeutic use

A
  • prophylaxis of organ rejection renal, cardiac,hepatic
  • used in combination : calcineurin inhibitor+ MMF+ GC
  • has largely replaced azathioprine in transplantation rejection prophylaxis
  • prophylaxis / treatment GVHD
  • treatment of psoriasis , lupus,Myasthenia graves
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9
Q

Mycophenolate mofetil toxicities

A 
Leukopania
Pure red cell a plasia
Malignancy risk
Diarrhea
Nausea/vomiting
Congenital anomalies in pregnancy
Drugs that cause additive toxicities
Absorption - antacids, cholestyramine
Competition for tubular secretion - probenecid
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10
Q

Azathioprine MOA

A
  • antimetabolite
    Metabolism- xanthine oxidase and TPMT. Those deficient in TPMT at risk of severe life threatening myelosupression
    6 MP-> TIMP
    6-TIMP->MeMPN-> inhibit phosphoribosyl-pyrophosphate amidotransferase-> inhibits de novo purine synthesis
    6-TIMP->6-TGMP ->6 TGTP-> 6TGTP is incorporated into DNA of proliferating cells-> induces strand break and mispairing -> apoptosis
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11
Q

Azathioprine therapeutic use

A

-prophylaxis of organ rejection used in combination calcineurin inhibitor and AZA and glucocorticoid
-RA
Inflammatory bowel disease
Acute glomerulonephritis

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12
Q

Azathioprine toxicities\ drug interactions

A 
Bone marrow suppression - leukopenia
Hepatoxicity- esp in patients with preexisting hepatic dysfunction
Inc malignancy & infection
Acute pancreatitis
Skin rash
Diarrhea
Nausea
SAFE IN PREGNANCY
allopurinol/febuxostat xanthine inhibitor —> aza inactivation, increased AZA toxicity
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13
Q

Belatacept MOA

A
  • selective T cell costimulation blocker
  • binds to cd80(b71) and cd86 (b72) & blocks stimulation-> inhibits T cell activation cytokine production and proliferation.
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14
Q

Belatacept therapeutic uses

A

Maintenance therapy for prophylaxis of acute organ rejection in kidney transplant patients who are seropositive for EBV
Combination with basitliximab mycophenolate, and corticosteroid

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15
Q

Belatacept adverse effects

A

Post transplant lymphoproliferative disorder (PTLD) and other malignancies

PML or other serious infections

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16
Q

Sirolimus MOA

A

Serum levels should be monitored after start of therapy and dose adjustments Bcus bioavailability difference in each patient
- mTOR inhibitor.drug-FKBP-12-mTOR-> cell cycle arrest in G1-S phase
Inhibit cell growth, proliferation , angiogenesis, and metabolism

17
Q

Mtor inhibitor therapeutic effect

A

Renal transplant w/reduced dose calcineurin inhibitor and glucocosteroid
CN sparing regime: cyclosporine tapering after 4-8 weeks only in patients with low to moderate immunologic risk

Cardiac and lung transplantation
Caution: delay treatment until surgical wound heals ( associated with bronchial anastomotic dehiscence first 30-90 days )
GVHD prevention and treatment
Drug eluting coronary stents to inhibit local cell proliferation and blood vessel occlusion
USE IN HEPATIC ALLOTRANSPLANTS ASSOCIATED WITH HELATIC ARTERY STENOSIS AND MORTALITY

18
Q

Sirolimus toxicity

A

Myelosuppression- thrombocytopenia,anemia,leukopenia

Impaired wound healing, wound dehiscence. May decreased production of growth factors of angiogenesis, fibroblast proliferation

Hepatoxicity ( fatal hepatic necrosis has occurred )

Inc triglycerides, inc cholesterol ( dose dependent)

Peripheral edema, lymphedema, pleural effusion, pericardial effusions, pneumoitis

Diarrhea nausea vomiting headache arthalgia aphthous ulcers, acne

19
Q

Sirolimus drug interactions

A

Cyp3A4 inducers and inhibitors

Cyclosporine or tacrolimus+ sirolimus - inc cni. Nephrotoxicity with deterioration of renal function.
Worsening dyslipidemia, esp hypertriglyceridema
Cyclosporine May inc risk of CNI induced hemolytic uremic syndrome
May inc sacrolimus conc. ->Inc risk of toxicity. Monitor serum blood levels,

Tacrolimus + sacrolimus competition at CYP3A4 , P-gp

medical school midcomp 5 (11 decks)

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