Drugs and pregnancy



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ETANERCEPT (Enbrel®, 1998)

  • Etanercept is a genetically engineered recombinant fusion protein that has the soluble form of the TNF receptor (p75) attached to the Fc portion of human IgG1 and as a consequence forms dimeric agent that binds TNF macintosh hd:users:elisafuray:desktop:screen shot 2013-04-23 at 4.58.03 pm.png

  • ADMINISTRATION

    • Etanercept is injected subcutaneously twice per week and inhibits the 
action of TNF by competing for soluble TNF.

    • Used with or without methotrexate

  • INFLIXIMAB (Remicade®, 1998)

    • Infliximab is a genetically engineered chimeric (man (Fc portion is human)-mouse) monoclonal antibody against TNF. Binds soluble/free and membrane associated TNF. macintosh hd:users:elisafuray:desktop:screen shot 2013-04-23 at 4.58.51 pm.png

    • INDICATIONS

      • It is also been approved for the treatment of Moderate to severe Crohn’s disease and ulcerative colitis.

    • ADMINISTRATION

      • IV infusions are administered every 8 weeks.

      • In RA, it is administered with methotrexate, which appears to limit the generation of antibodies against infliximab that otherwise reduce the benefits of subsequent treatments

  • ADALIMUMAB (Humira®, 2002)
macintosh hd:users:elisafuray:desktop:screen shot 2013-04-23 at 5.00.49 pm.png

    • Similar to infliximab except it is a human-human antibody against TNF and administered more frequently

    • INDICATIONS

      • RA, AS, psoriatic arthritis, psoriasis, and also Crohn’s Disease, and ulcerative colitis (IBD)

    • ADMINISTRATION

      • SC injection, 1x per 2 weeks (t1⁄2 = 2 wks)

      • Used with or without methotrexate (MTX)

  • CERTOLIZUMAB (Cimzia®, 2008)


    • Anti-TNF human Fab antibody fragment conjugated to pegolmacintosh hd:users:elisafuray:desktop:screen shot 2013-04-23 at 5.03.46 pm.png

    • ADMINISTRATION AND USE

      • SC injection, 2x 200 mg per 4 weeks (t1⁄2 = 2 wks)—longer half life

      • Used with or without methotrexate (MTX)

      • Indicated for RA and Crohn’s Disease

  • GOLIMUMAB (Simponi®, 2009)

    • MECHANISM

      • Anti-TNF human antibody

    • ADMINISTRATION AND USE

      • SC injection, 1x per 4 weeks (t1⁄2 = 2 wks)

      • Used with methotrexate (MTX)

      • Indications RA, ankylosing spondolyitis, psoriatic arthritis

  • TNFBLOCKERS: WARNINGS AND ADVERSE EFFECTS

    • IMMUNOSUPPRESSION (compare with use of glucocorticoids)

      • Serious infections and sepsis seen - 0.04 per patient year - some fatal

        • Tuberculosis – 13 cases during clinical trials

          • Evaluate for active or latent TB before initiation of tx—because it can be reactivated if you suppress your immune system

        •  risk of Invasive opportunistic fungal infections – 6 cases

        • Upper respiratory tract infection 1 per patient yr

        • Initiation of treatment is contraindicated if patient has active infection or patient has recurrent infections

        • Live vaccines contraindicated with TNF blockers

      • Neurologic events

        • Rare cases of exacerbation of demyelinating diseases, e.g. multiple sclerosis

      • Malignancies in children - under investigation

        • 30 cases in children/young adults 1998-2008

          • Incidence of lymphoma (~50%) (10/2468) higher than in general population – link to anti-TNF therapy?

            • Immune system helps protect us from infection and also plays a role in preventing cancer in our bodies

        • FDA continues to receive reports of hepato-splenic T-cell lymphoma (HSTCL) most with IBD (4/14/2011)

      • Autoimmunity

        • ANA titers may increase during therapy

          • lupus-like syndrome possible

      • Antibodies against drug


        • Decreased by methotrexate, azathioprine, etc

  • DRUGS THAT TARGET INTERLEUKINS

    • ANAKINRA (Kineret®, 2001)

      • Recombinant, human IL-1 receptor antagonist (IL-1Ra), (a 153 amino acid protein), which binds to the IL-1 receptor and prevents IL-1 from binding.

        •  IL-1 effects

      • USE: Treatment of Rheumatoid arthritis

        • For moderate-severe R. Arthritis if inadequate response to DMARDs, 
+ or – MTX, etc

        • Not to be used with TNF blockers, because both  immune system functioning  increases frequency of infections

      • ADMINISTRATION

        • SC injection 1 per day (half-life = 4-6 hours)

      • ADVERSE EFFECTS: risk of infections, (no live vaccines should be used), neutropenia, most common is injection site reaction

    • TOCILIZUMAB (Actemra®, 2010)


      • Humanized monoclonal antibody against soluble and membrane IL-6 receptors – blocks signaling, e.g. OCs

        • IL-6 has been shown to be important in activating osteoclasts which break down bone

      • INDICATIONS and ADMINISTRATION

        • Adults:
moderate -severe RA not responsive to TNF antagonists 


          • IV infusion every 4 weeks + or – MTX

        • Children > 2 y.o.

          • systemic juvenile idiopathic arthritis (SJIA)
- IV infusion every 2 weeks

      • ADVERSE EFFECTS:

        • Infections/malignancy

        • GI perforations in patients with diverticulitis

        • Hyperlipidemia

        • Symptoms of demyelination

    AGENTS THAT TARGET T-CELL AND INTERLEUKIN 2 (IL-2)

    • IL-1 is secreted by the APC and IL-2 is important in the maturation and division of proliferation of active T-cells

    • USES

      • Suppression of immune and inflammatory response

        • Prevent rejection of transplants—more important for this

        • Autoimmune/inflammatory diseases

    • AGENTS THAT TARGET T-CELLS

      • Useful in suppression of immune and inflammatory response, preventing rejection of transplants and treating autoimmune/inflammatory diseases.

      • CYCLOSPORINE (Neoral®, Sandimmune®, 1983)

        • Cyclic hydrophobic (very) peptide produced by fungiBeauveria nivea

          • Very high partition coefficient—high enough that our GI tract has trouble absorbing them—need to dissolve them in an ethanol mix to try and get some uniform absorption

        • USES

          • Prevent rejection in renal, liver and heart transplants VERY IMPORTANT

          • Autoimmune diseases RA, IBD, myasthenia gravis

          • Can be used in conjunction with glucocorticoids (prednisone) and azathioprine (or could replace this w/ mycophenolate which has fewer side effects)

        • MECHANISM

    macintosh hd:users:elisafuray:desktop:screen shot 2013-04-22 at 3.23.31 pm.png

          • T-cells get activated by the APC (w/ second signal from B7 on APC and CD28 on T-cell   Ca). Signal transduction involves an increase in cytosol Ca2+, which activates calcineurin (Cal), a phosphatase that dephosphorylates NF-AT (nuclear factor of activated T-cells)—the phosphate normally hides the target sequence that can allow it to go into the nucleus. NF-AT can now enters the nucleus and turns on synthesis of cytokines such as interleukin-2 and its receptor, which induces T-cell proliferation. Cyclosporine binds to a cyclophilin (CP) and inhibits calcineurin, thus inhibiting T-cell activation/proliferation

            • so blocks formation and activity of IL-2

        • PHARMACOKINETICS

          • ADMINISTRATION

            • Due to insolubility in water, it is usually administered orally as solution in an ethanol/corn oil/castor oil derivative mix in capsules or diluted into orange or apple juice to produce a “microemulsion”

              • Gut liver where it is a substrate for the P450 system oxidation and also a substrate for P-gp so this can  absorption by kicking it back into the gut and into the bile

            • Variable absorption 20-50% -Neoral® > Sandimmune®

            • 1st pass metabolism significant - metabolized by CYP3A4 and 
substrate for P-gp (kicks hydrophobic things out of cells)

              • it is a hydrophibic substance so its not surprising that its metabolized by P450 system

            • Many drug interactions

            • Significant toxic effects

              • Assay levels in the blood to make sure patient is getting the right dose

            • IV: only if oral administration not possible

          • RESULT: Need to assay blood levels to establish appropriate dose

        • TOXICITY

          • Nephrotoxicity most common and important (20-38% in allografts). Difficult to distinguish from kidney rejection in kidney transplant patients

          • Others


            • Hypertension

            • Hirsutism

          • Little effect on bone marrow

            • Mant of the cytotoxic drugs (like azathioprine) do have toxic effects on bone marrow so you don't really want 2 drugs with same side effects b/c it  the likelihood of them occurring

        • DRUG INTERACTIONS - IMPORTANT –b/c narrow therapeutic window

          • Drugs that inhibit CYP3A4 or P-glycoprotein may potentiate toxicity

            • ketoconazole, itraconazole, (antifungals)

            • erythromycin, clarithromycin, grapefruit juice (esp in GI tract), etc.

            • Ritonavir is most efficacious inhibitor of CYP3A4

            • Cyclosporin itself inhibits CYP3A4

          • Drugs that induce the CYP3A4 or P-gp may lead to organ rejection b/c will be metabolized faster and level of drug in the body will 

            • Phenobarbital - CNS depressant

            • Carbamazepine - anticonvulsant

            • Phenytoin-anticonvulsant

            • Rifampin - antimicrobial used for tx Tb

            • St. John’s Wort - dietary supplement - “antidepressant”

          • Other nephrotoxic drugs

            • e.g. amphotericin B, aminoglycosides, NSAIDs etc


          • Cyclosporine can inhibit metabolism of drugs by blocking CYP 3A4

            • E.g. lovastatin – increases risk of rhabdomyolysis

      • TACROLIMUS (FK506, Prograf®, 1994)

        • Another hydrophobic cyclic compound produced by fungi that inhibits calcineurin—it is very similar to cyclosporin

          • Properties very similar to cyclosporine, BUT has different receptor - “FK binding protein” (FKBP25)  inhibition of IL-2 production and IL-2 receptor production

          • Approved for heart, liver and kidney transplants to  rejection

          • Used topically for treating eczema

      • SIROLIMUS (Rapamune®, 1999)

        • Another hydrophobic cyclic compound, related to tacrolimus produced by another fungi, BUT different mechanism and little nephrotoxicity, hence it is used synergistically with cyclosporine and prednisone.

        • MECHANISM

          • Binds to a “FK binding protein”, FKBP12, but unlike cyclosporine and tacrolimus it does NOT block calcineurin or IL-2 production

            • It acts at a later step

          • Block a kinase “mTOR” – a kinase involved in cell cycle

            • mTOR= Mammalian Target Of Rapamycin—this is a receptor

          • Blocks T-cell proliferation induced by cytokines

          • Blocks B-cell proliferation and differentiation into Ig producing cells

          • Blocker proliferation of endothelial and SM cells –so also used for coating stents

        • USE

          • Prophylaxis of renal transplant rejection

          • Is used in combination with cyclosporine and corticosteroids –they act at different steps in the pathway

          • Not for liver transplant - hepatic artery thrombosis risk

        • SIDE EFFECTS

          • Little nephrotoxicity alone, But, sirolimus aggravates CSA (cyclosporine)-induced renal dysfunction (makes CSA nephrotoxicity worse!)

          • Triglycerides and cholesterol increase (51%, 44%) and further increased by concomitant use of CSA (cyclosporin A= cyclosporine)

            • All patients should be monitored for hyperlipidemia

            • 50% patients will need treatment

            • When risk is minimal—use both drugs together and then once there is a  chance of rejection wean the patient off the CSA and continue treatment w/ Sirolimus

          • Increased BP

          • Thrombocytopenia (37%) –blocks proliferation of a lot of cells

        • DRUG INTERACTIONS -

          • Bioavailability is only 14% and metabolized via CYP 3A4, hence susceptible to drug interactions, e.g. cyclosporine (CSA inhibits its metabolism so levels of it will  in the blood)

          • In addition to CSA, many drug interactions possible

            • Sirolimus normally administered 4 hr after CSA

              • Don't administer simultaneously

          • Monitoring may be necessary

        • ADMINISTRATION

          • Not soluble in water must be dissolved in an oil base

          • Administered mixed with water or orange juice, NOT grapefruit

      • ABATACEPT (Orencia®, 2005)


        • Normal physiology

          • To prevent over proliferation of T cells the T cell has a soluble receptor for B7 which binds to B7 (binds a lot more strongly to B7 than CD28 does!) so this is produced by the proliferating T cells and will eventually turn off T cell proliferation

            • If you knock this out the animal dies—it's a lethal mutation

        • CTLA4 soluble B7 receptor attached to Fc of IgG1


          • ABATACEPT is a Recombinant form of this soluble B7 receptors attached to an antibody

        • CTLA4 is a natural B7 antagonist binds 20x more strongly than CD28.

        • ACTION
 Inhibits T-cell proliferation

        • INDICATION

          • Rheumatoid arthritis if inadequate response to MTX or TNF antagonists

            • Should not be used with TNF antagonists (infliximab, etc)

          • Not recommended for use with anakinra (IL-1 inhibiting drug)

      • DACLIZUMAB (Zenapax®, 1997) and BASILIXIMAB (Simulect®, 1998)

        • Drugs for prophylaxis of acute rejection of renal transplants

        • MECHANISM

          • Chimeric mouse/human monoclonal antibodies against IL-2 receptor on activated T-cells

            • Antibodies against the IL-2 receptor

        • INDICATION:


          • Prevention of rejection of renal transplants used with CSA and corticosteroids


            • These are used SHORT TERM (days or weeks after surgery)

        • ADMINISTRATION (IV)

          • Daclizumab before surgery and 4 doses at 2 wk intervals

          • Basiliximab 2 hr before surgery and 4 days after transplantation


    DRUGS FOR GOUT

    • PATHOGENESIS of GOUT

      • What is gout?
A disease that results from hyperuricemia

      • What is “hyperuricemia”?
– Too much uric acid in the blood

      • What is uric acid? It is a waste product from the breakdown of purines (Adenine and guanine)

    • URIC ACID macintosh hd:users:elisafuray:desktop:screen shot 2013-04-23 at 11.31.46 pm.png

      • Uric acid is product of oxidation of purine bases from de novo synthesis, tissue DNA, and diet

      • Normally, 600-800 mg/day produced/excreted

      • Normal plasma urate 6.8 mg/dL men, 6 women

      • Risk of gout if plasma urate > 7 mg/dL

        • More common in men than women

      • ELIMINATION of URIC ACID

        • Has low water and lipid solubility

          • Solubility of uric acid is low the lower the pH and most peoples urine tends to be on the acidic side—which makes this problem worse

        • 25-33% eliminated in GI tract - metabolized by bacteria in the colonmacintosh hd:users:elisafuray:desktop:screen shot 2013-04-23 at 11.32.46 pm.png

        • Rest is eliminated by kidney (300-600 mg/day)

          • Uric acid get filtered at the glomerulus (GFR= 125 ml/min) and as we get further along in the renal tubules we reabsorb stuff and get the volume down to 1 ml/min which will result in very concentrated uric acid. Uric acid is not soluble so it will ppt and clog up the kidneys renal failure. BUT 90% of it gets reabsorbed

          • Filtration rate = GFR, but only 10% filtrate is excreted

            • Why? Active reabsorption occurs in proximal tubule

        • Significant amounts are secreted by pumps in PT

        • Second active absorption site

        • There is very little passive non-ionic reabsorption

        • If amount in urine exceeds solubility, uric acid crystals/stones form in CD - nephrolithiasis

    • HYPERURICEMIA:
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