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

          • 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:

      • CAUSED BY

        • Increased production of uric acid

        • Decreased excretion of uric acid

        • Or Combination of both

      • PRIMARY GOUT

        • More common in men (10x), genetic links

        • Risk increases with age, body weight, alcohol, diet

      • SECONDARY GOUT

        • Drug induced, e.g. diuretics

          • Thiazide diuretics especially—they compete with uric acid for secretion into the tubule—so  amount that get into the kidney and leading to  levels in the blood

        • Chemotherapy of cancer kills cells  big influx of DNA (purines)   purine metabolism  uric acid

      • CONSEQUENCES

        • ACUTE GOUTY ARTHRITIS macintosh hd:users:elisafuray:desktop:screen shot 2013-04-23 at 11.36.05 pm.png

          • Uric acid enters the synovial fluid of the joints where the pH tends to be acidic. Uric acid forms Crystals of Na urate in joint and cause inflammatory cells (macrophages, etc) to come in an try and eliminate these crystals and this activates macrophages which release TNF, IL-1, PG’s, LTB4, etc.

          • Often affects big toe (metatarsophalangeal joint)

            • gouty toe

            • WHY? thought to be because they are a little bit cooler and the  temperature  likelihood that these crystals will form

          • Attacks often begin during night with extreme pain

            • Last hours–days if not treated

            • Occurrence at night is thought to be because you’ve been standing on your foot all day long and the  pressure of the joints  influx of more synovial fluid   risk of uric acid getting into the joints  at night we lie down and that pressure and fluid starts to dissipate back into the blood and the uric acid gets concentrated and triggers an attack

          • May progress to chronic nonsymmetric synovitis (kind of like rheumatoid arthritis)

          • extremities-gout

            • Hyperalgesia!!! Often begins in the night

              • PG’s produce hyperalgesia!!

        • TOPHACEOUS GOUT – late complication

          • After prolonged hyperuricemia, tophi - large gritty deposits of uric acid crystals - form in connective tissue, tendons, SC

          • Tophi can damage joint and neighboring soft tissues, e.g. nerve compression ® carpal tunnel syndrome

          • gout_fig7 hand gout2 hand gout

        • NEPHROLITHIASIS (10-25% patients)

          • Especially if urine concentrated—so drink a lot of water to  concentration

          • Especially if urine has low pH—Na-bicarbonate to  pH of urine (take an antacid)

          • Especially if renal excretion exceeds 1100 mg/day

        • GOUTY NEPHROPATHY
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