Immunosuppressive Agents--Regel

Question 1

Diphenhydramine

Chlorpheniramine

Answer 1

MOA: H1, mAChR, α-adrenergic, 5-HT antagonist

Distribution: CNS penetrant, PO, P-glycoprotein resistant

Metabolism: inactivated in liver, excreted in urine

Adverse: sedation, secretion drying (anti-mAChR), acute like atropine tox, allergic dermatitis

Question 2

Diphenhydramine

vs

Chlorpheniramine

for motion sickness

Answer 2

dephenhydramine

Question 3

Diphenhydramine

vs

Chlorpheniramine

for daytime use

Answer 3

chlorpheniramine

less sedating

Question 4

Ceterizine

Fexofenadine

Loratidine

Answer 4

MOA: H1 antagonist (no anti-cholinergic)

Distribution: less CNS penetration (less sedating), P-glycoprotein sensitive

Met/Elim: met in liver, renal excretion

Adverse: not cardiotoxic

Question 5

NSAIDs

Answer 5

MOA: COX1/2 inihbitors

TU:

• analgesia (PG lower pain threshold)
• antipyrentic (decreases PGE2 synthesis)
• anti-inflammatory

Adverse: gastic ulceration, gestation prolongation, nephrotoxicity, hepatotoxicity, increased bleeding time–prolonged PTT

Question 6

Acetylsalicylate

Answer 6

MOA: irreversibly binds/inhibits COX

Adverse: aspirin hypersensitivity (not antibody-mediated), Reye’s syndrome–esp. children with chickenpox

Question 7

Indomethicin

Answer 7

MOA: COX inhibitor

*most potent*

Question 8

Peroxicam

Answer 8

MOA: COX inhibitor

PK: PO once daily

Adverse: dose-related serious GI bleed

Question 9

Celecoxib

Answer 9

MOA: COX2 inhibitor

Adverse: no effect on thromboxane, thrombus

Question 10

Acetaminophen

Answer 10

MOA: COX inhibitor mostly in brain

TU: analgesic, antipyretic, not anti-inflammatory

Toxicity: hepatotoxicity at high doses

*650 mg just as effective as 1000 mg*

Question 11

What is the TU for leukotriene inhibitors?

Answer 11

asthma prophylaxis

Question 12

Zileuton

Answer 12

MOA: 5-lipoxygenase antagonist, prevents LTB₄ and peptide leukotrienes

PK: liver cytochrome P450s, drug-drug

Adverse: hepatotoxic

Question 13

Zafirlukast

Answer 13

MOA: leukotriene receptor antagonist (P450 isoenzyme), LTD₄ receptor (Cys LTR1)

Adverse: drug-drug

Question 14

Montelukast

Answer 14

MOA: leukotriene receptor antagonist (LTR₄, Cys LTR1)

PK: once daily

*first choice leukotriene inhibitor*

Question 15

Steroids

MOA

(cortisone, hydrocortisone, betamethasone, dexamethasone, methylprednisalone, prednisone)

Answer 15

MOA:

glucocorticoid receptor, glucocorticoid response element (GRE)

interacts with NF-kB and AP1

• reduce COX2 expression-
• inhibit arachadonic acid release –> decreased prostaglandins and leukotrienes-
• inhibit degranulation of basophils/mast cells-
• inhibit release of TNF, IL-1, IL-2, IFN

Question 16

Steroids and WBC

Answer 16

Neutrophils: steroids promote demarginalization of neutrophils, promote release from BM, and increase neutrophilic t_1/2 in blood –> neutrophilia

Lymphocytes: profound transient lymphopenia, cells migrate out of the blood into lymphoid tissue

Question 17

Anti-inflammatory | Sodium Retention | Duration

Cortisone

Hydrocortisone

Answer 17

Anti-inflammatory: +

Sodium retention: +

Duration: short

Question 18

Anti-inflammatory | Sodium Retention | Duration

Betamethasone

Dexamethasone

Answer 18

Anti-inflammatory: ++

Sodium retention: –

Duration: long

Question 19

Anti-inflammatory | Sodium Retention | Duration

Methylprednisalone

Prednisone

Answer 19

Anti-inflammatory: +

Sodium retention: ±

Duration: intermediate

Question 20

Glucocorticoid distribution

Answer 20

PO, IV, topical, or inhaled (complete first pass metabolism)

Question 21

Glucocorticoid metabolism

Answer 21

hepatic metabolism

renal excretion

Question 22

Calcineurin inhibitors

Answer 22

cyclosprorin

tacrolimus

Question 23

Cyclosporin

Answer 23

MOA: cyclophilin receptor antagonist in cytosol–> decreased calcineurin activity –> inhibits cytokine gene expression and T-cell activation

PK: hepatic metabolism, drug-drug

Toxicity: nephrotoxicity (75% of patients), must delineate from rejection

Question 24

Tacrolimus

Answer 24

MOA: binds FK506 binding protein –> inhibits calcineurin activity –> decreases T-cell activaiton

Tox: nephrotoxicity

Question 25

Sirolimus

Answer 25

**_MOA_**: binds FK-binding protein --\> inhibits mTOR --\> blocks G₁ -\> progression **_PK_**: CYP3A4 substrate --\> drug/drug **_Adverse_**: nephrotoxic w/ cyclosporin, increased infection and lymphoma risk, increased triglycerides

Question 26

Mycophenolate Mofetil

Answer 26

**_MOA_**: inhibits inosine monophosphate dehydrogenase (IMPDH) --\> inhibits *de novo* guanisine synthesis --\>B- and T-cells depend on this pathway, so becomes _antiproliferative_ **_Toxicity_**: leukopenia, diarrhea, vomitting

Question 27

Anti-Thymocyte Globulin

Answer 27

**_MOA_**: binds thymocytes (hematopoietic progenitor cells) **_TU_**: prevents solid organ rejection by decreasing ciruculating lymphocytes **_Adverse_**: serum sickness, nephritis, anaphylaxis

Question 28

Muromonab-CD3

Answer 28

**_MOA_**: anti-CD3, cell internalizes TCR complex **_TU_**: prevents rejection of solid organ transplants **_Adverse_**: cytokine release syndrome, HAMA reactions

Question 29

Daclizumab

Answer 29

**_MOA_**: anti-CD25 (IL2R) --\> block IL-2 mediated T-cell proliferation and activation **_TU_**: solid organ rejection prophylaxis **_Adverse_**: no cytokine release syndrome, lower risk of lymphoproliferative disorders, anaphylaxis

Question 30

Basiliximab

Answer 30

**_MOA_**: anti-CD25 (IL2R) --\> block IL-2 mediated T-cell proliferation and activation **_TU_**: solid organ rejection prophylaxis **_Adverse_**: no cytokine release syndrome, lower risk of lymphoproliferative disorders, anaphylaxis