Immunosuppressants
| Drug: Prednisone (generic, Meticorten ®) |
| Drug Class: Glucocorticoid (synthetic) |
| Mechanism of Action: Effects are mediated by binding to glucocorticoid receptors. When stimulated, these receptors alter the transcription of various target genes. In the absence of the hormonal ligand, glucocorticoid receptors are primarily cytoplasmic & exist as oligomeric complexes with heat shock proteins. When free hormone in the cytoplasm binds to the receptor, a conformational change occurs and it dissociates from heat shock protein. The hormone-receptor complex is transported to the nucleus, where it interacts with DNA and nuclear proteins. They inhibit the production of inflammatory mediators, including PAF, leukotrienes, prostaglandins, histamine and bradykinin. A mechanism that contributes to the decrease in the synthesis of inflammatory mediators produced by glucocorticoids is an inhibition of phospholipase A2 as well a downregulation of the expression of Cox-2 (but not Cox-1), thus reducing the amount of enzyme available to produce prostaglandins. By inhibiting IL-1 production by monocytes, they cause a decrease in IL-2 and IFN-gamma production. Although cellular immunity is affected more than humoral immunity, the primary antibody response can also be diminished. Continuous administration increases the catabolic rate of IgG, the major class of antibody immunoglobulins. |
| Indications: used for its potent anti-inflammatory effects in disorders of many organ systems. Used alone or in conjuction with other immunosuppressive agents to prevent transplant rejection. Used to minimize allergic reactions that may occur with the use of monoclonal antibodies & to treat autoimmune diseases. Prednisone is one of the most commonly used immunosuppressants. |
| Contraindications: Systemic fungal infections and known hypersensitivity to components of the drug formulation. Persons who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chicken pox or measles. |
| Pharmacokinetics: Prednisone is rapidly converted to the active product prednisolone in the body. Prednisone has an intermediate duration of action compared to other glucocorticoids. |
| Side Effects: High-dose, long-term glucocorticoid therapy can produce severe toxicities that can include effects such as sodium retention, fluid retention, muscle weakness, steriod myopathy, loss of muscle mass, osteoporosis, tendon rupture, particularly of the Achilles tendon, peptic ulcer with possible perforation and hemorrhage; pancreatitis, impaired wound healing, thin fragile skin, menstrual irregularities; development of Cushingoid state; secondary adrenocortical and pituitary unresponsiveness, posterior subcapsular cataracts, increased intraocular pressure, glaucoma, growth inhibition, diabetogenesis & psychoses just to name a few. |
| Notes: Corticosteroids may mask some signs of infection, and new infections may appear during their use |
References: www.rxlist.com, Katzung's text (see Chapters 39 &56) & Goodman & Gillman's 10th Edition (Chapter 26). |
| Drug: Cyclosporine (Sandimmune, Neoral, SangCya ®) |
| Drug Class: Immunosuppressant |
| Mechanism of Action: Cyclosporine is a fat-soluble cyclic polypeptide antibiotic that acts at an early stage in the antigen receptor-induced differentiation of T cells and blocks their activation. Cyclosporine binds to and forms a complex with the intracellular protein cyclophilin, resulting in the inhibition of calcineurin, a phosphatase that is necessary for activation of a T cell-specific transcription factor (NF-AT). NF-AT is involved in the synthesis of interleukins (e.g. IL-2) by activated T cells. In vitro studies indicate that cyclosporine inhibits the gene transcription of IL-2, IL-3, IFN-gamma, and other factors produced by antigen-stimulated T cells. Cyclosporine produces a specific and reversible inhibition of immunocompetent lymphocytes in the G0-or G1-phase of the cell cycle. T-lymphocytes are preferentially inhibited. The 1-helper cell is the main target, although the 1-suppressor cell may also be suppressed. |
| Indications: a potent immunosuppressive agent which in animals prolongs survival of allogeneic transplants involving skin, heart, kidney, pancreas, bone marrow, small intestine, and lung. |
| Contraindications:known drug hypersensitivity to the product |
| Pharmacokinetics: can be given orally or i.v. The absorption of cyclosporine from the gastrointestinal tract is incomplete and variable.Metabolized by P-450 isoforms & excreted in the bile. Elimination half life is 24 hrs. |
| Side Effects: Numerous toxicities, including - nephrotoxicity, hypertension, hyperglycemia, liver dysfunction, hirsutism, gum hyperplasia. |
| Major drug interactions: Numerous! Drugs That Exhibit Nephrotoxic Synergy: gentamicin, amphotericin B, cimetidine, trimethoprim with sulfamethoxazole, tobramycin, ketoconazole, ranitidine, vancomycin, melphalan, diclofenac, azapropazon. Drugs That Increase Cyclosporine Levels (P-450 inhibitors): diltiazem, ketoconazole, danazol, erythromycin, nicardipine, fluconazole, bromocriptine, methylprednisolone, verapamil, itraconazole, metoclopramide, amphotericin B. Drugs That Decrease Cyclosporine Levels (P-450 inducers): rifampin, phenytoin, phenobarbital, carbamazepine. |
References: www.rxlist.com |
| Drug: Tacrolimus [FK506] (Prograf ®) |
| Drug Class: Immunosuppressant macrolide antibiotic |
| Mechanism of Action: tacrolimus binds to the immunophilin FK-binding protein (FKBP), forming a complex, and results in the inhibition of calcineurin, which is necessary for the activation of the T-cell specific transcription factor NF-AT. Its mechanism is "similar" to cyclosporine in that its mechanism involves the inhibition of calcineurin. |
| Indications: The same as for cyclosporine - inhibiting immune responses in organ transplantation. Also used as a topical treatment for atopic dermatitis & psoriasis. |
| Contraindications: known hypersensitivity to this preparation, including HCO-60 (polyoxyl 60 hydrogenated castor oil). |
| Pharmacokinetics: oral or i.v. administration. Metabolized by P-450 (CYP3A) w/ the potential for drug interactions. |
| Side Effects: tremor, headache, diarrhea, hypertension, nausea, and renal dysfunction. |
| Major drug interactions: Due to the potential for additive or synergistic impairment of renal function, care should be taken when administering tacrolimus with drugs that may be associated with renal dysfunction.Tacrolimus is metabolized mainly by CYP3A. Substances known to inhibit or induce this enzyme may decrease or increase the metabolism of tacrolimus with resultant changes in plasma concentrations (see rxlist.com for further details). Immunosuppressants may affect vaccination. Therefore, during treatment with Prograf, vaccination may be less effective. |
| Notes: increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression |
References: www.rxlist.com |
| Drug: Sirolimus [rapamycin] (Rapamune ®) |
| Drug Class: Immunosuppressant |
| Mechanism of Action: Sirolimus inhibits T lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (Interleukins IL-2, IL-4, and IL-15) stimulation by a mechanism that is distinct from that of other immunosuppressants. Sirolimus also inhibits antibody production. In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex. The sirolimus:FKBP-12 complex has no effect on calcineurin activity. This complex binds to and inhibits the activation of the mammalian Target Of Rapamycin (mTOR), a key regulatory kinase. This inhibition suppresses cytokine-driven T-cell proliferation, inhibiting the progression from the G 1 to the S phase of the cell cycle (see figure 5 in Dr. Beckman's handout). |
| Indications: the prophylaxis of organ rejection in patients receiving renal transplants. It can be used in combination with other immuosuppressants (cyclosporine, tacrolimus, glucocorticoids). Topical sirolimus is used in some dermatologic disorders & in combination with cyclosporine in the management of uveoretinitis. |
| Contraindications: patients with a hypersensitivity to sirolimus or its derivatives or any component of the drug product. |
| Pharmacokinetics: Sirolimus is a substrate for both cytochrome P450 (CYP3A4) and P-glycoprotein. |
| Side Effects: Toxicities can include profound myelosuppression (esp. thrombocytopenia), hepatotoxicity, diarrhea, hypertriglyceridemia & headache. |
| Major drug interactions: The pharmacokinetic interaction between sirolimus and concomitantly administered drugs is based upon drugs that effect CYP3A4 and P-glycoprotein activity (see rxlist.com). |
References: www.rxlist.com & Katzung's text |
Cytotoxic Drugs
| Drug: Azathioprine (generic, Imuran ®) |
| Drug Class: Immunosuppressant |
| Mechanism of Action: an immunosuppressive antimetabolite. It interferes with purine nucleic acid metabolism at steps required for lymphoid cell proliferation that follows antigenic stimulation. The purine analogs are thus cytotoxic and destroy stimulated lymphoid cells. Cellular immunity as well as primary and secondary serum antibody responses can be blocked by these agents. |
| Indications: an adjunct for the prevention of rejection in renal homotransplantation. It is also indicated for the management of severe, active rheumatoid arthritis unresponsive to rest, aspirin or other nonsteroidal anti-intlammatory drugs, or to agents in the class of which gold is an example |
| Contraindications: should not be used to treat rheumatoid arthritis in pregnant women. Patients with rheumatoid arthritis previously treated with alkylating agents cyclophosphamide, chlorambucil, melphalan or others) may have a prohibitive risk of neoplasia if treated with azathioprine. |
| Pharmacokinetics: Azathioprine is a prodrug that is metabolized to mercaptopurine (the active form). Xanthine oxidase splits much of the active material to 6-thioruric acid prior to excretion in the urine. |
| Side Effects: hematologic (leukopenia and/or thrombocytopenia) and gastrointestinal (nausea & vomiting). The risks of secondary infection and neoplasia are also significant. |
| Major drug interactions: Patients taking allopurinol should have the dose of azathioprine reduced to one third to one forth the usual amount to prevent toxicity. |
References: www.rxlist & Katzung's text |
| Drug: Cyclophosphamide (Cytoxan, Neosar ®) |
| Drug Class: Immunosuppressant |
| Mechanism of Action: an alkylating agent that is one of the most efficacious immunosuppressive drugs available. Destroys proliferating lymphoid cells. Greater effect on B cells than on T cells. |
| Indications: effective against autoimmune disorders (systemic lupus erythematosus & multiple sclerosis) & in patients with autoimmune hemolytic anemia. Can inhibit an established immune response. Typically used as a drug of 2nd choice after another drug has been found to be ineffective (because of its greater toxicity). |
| Contraindications: patients with severely depressed bone marrow function |
| Side Effects: nausea, vomiting, electrolyte disturbances, cardiotoxicity |
References: www.rxlist & Katzung's text |
| Drug: Mycophenolate mofetil (CellCept ®) |
| Drug Class: Immunosuppressant |
| Mechanism of Action: a semisynthetic "prodrug" derivative of mycophenolic acid (the active form). It inhibits the de novo synthesis of purines by inhibiting inosine monophosphate dehydrogenase (IMPDH). It inhibits a series of T and B lymphocyte responses, including mitogen and mixed lymphocyte responses. |
| Indications: Renal & Cardiac Transplants. Indicated for the prophylaxis of organ rejection in patients receiving allogeneic renal transplants and in patients receiving allogeneic cardiac transplants. CellCept can be used concomitantly with cyclosporine and corticosteroids. |
| Pharmacokinetics: Mycophenolate mofetil is a prodrug that is hydrolyzed to mycophenolic acid. Administered as a prodrug to enhance bioavailability. |
| Side Effects: GI side effects, headache, hypertension and reversible myelosuppression (primary neutorpenia). |
References: www.rxlist & Katzung's text |
Antibody Reagents
| Drug: Anti-Thymocyte globulin [ATGAM] (Thymoglobulin ®) |
| Drug Class: Immunosuppressive antibody |
| Mechanism of Action: contains cyctotoxic antibodies that bind to molecules on the surface of human T lymphocytes. They can deplete circulating lymphocytes by direct cytotoxicity (complement & cell-mediated), and also block lymphocyte function by binding to cell surface molecules involved in the regulation of cell function. |
| Indications: 1) used in combination with other agents to treat acute rejection in kidney transplants; 2) prior to bone marrow transplantation to prevent graft-host reactions; 3) has induced remissions in aplastic anemia. |
| Pharmacokinetics: administered parenterally. |
| Side Effects: fever & chills |
References: Dr. Beckman's handout |
| Drug: Rho (D) Immune Globulin Micro-Dose (BayRho-D, RhoGam, Win-Rho ®) |
| Drug Class: Specific IgG Antibody to Rho (D) antigen of the red cell |
| Background: Rh-negative mothers can become sensitized to the D antigen on red cells in an Rho (D)-positive or Du-positive infant, when fetal red cells leak into the mother's blood stream during child birth. In subsequent pregnancies, maternal antibody against Rh-positive cells is transfered to the fetus during the 3rd trimester, leading to the development of hemolytic disease of the newborn. |
| Mechanism of Action: When injection of Rho(D) antibody is given to the mother 24-72 hrs after the birth of an Rh-positive baby, the mother's own antibody response to the foreign Rho (D)-positive cells is suppressed because the baby's red cells are cleared from the circulation before the mother can generate a B cells response against Rho(D). Therefore she has no memory B cells that can activate upon subsequent pregnancies with an Rho(D)-positive fetus. |
| Indications: prevention of Rh hemolytic disease of the newborn. |
| Pharmacokinetics: Given i.m. Note: Rho(D) is given to the mother, and NOT the infant. |
| Side Effects: infrequent local discomfort at the injection site, slight temperature elevation. |
References: Katzung's text. |
| Drug: Muromonab-CD3 [OKT3] (Orthoclone OKT3 ®) |
| Drug Class: Monoclonal Antibody |
| Mechanism of Action: A murine monoclonal antibody directed against the CD3 molecule on the surface of human thymocytes and mature T cells. Blocks both killing by cytotoxic T cells and several other T cell functions. |
| Indications: treatment of renal allograft rejection. |
References: Katzung's text |
| Drug: Infliximab (Remicade ®) |
| Drug Class: Monoclonal Antibody / TNF- alpha antagonist |
Mechanism of Action: neutralizes the biological activity of TNFalpha by binding with high affinity to the soluble and transmembrane forms of TNFalpha and inhibits binding of TNFalpha with its receptors. Biological activities attributed to TNFalpha include: induction of pro-inflammatory cytokines such as interleukins (IL) 1 and 6, enhancement of leukocyte migration by increasing endothelial layer permeabilityand expression of adhesion molecules by endothelial cells and leukocytes, activation of neutrophil and eosinophil functional activity, induction of acute phase reactants and other liver proteins, as well as tissue degrading enzymes produced by synoviocytes and/or chondrocytes. |
| Indications: Rheumatoid arthritis: in combination with methotrexate, is indicated for reducing signs and symptoms, inhibiting the progression of structural damage and improving physical function in patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to methotrexate. Crohn’s disease: for reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in patients with fistulizing Crohn’s disease. |
| Pharmacokinetics: parenteral administration |
| Side Effects: increased incidence of lymphoma |
References: www.rxlist & Katzung's text |
| Drug: Daclizumab (Zenapax ®) |
| Drug Class: Monoclonal Antibody / IL-2 Antagonist |
| Mechanism of Action: IgG1 that binds to CD25 (alpha subunit of the IL-2 receptor), blocking IL-2 from binding to activated lymphocytes, which is an immunosuppressive action. It functions as an IL-2 antagonist |
| Indications: prophylaxis of actue organ rejection in renal transplant patients. Usually combined with glucocorticoids & cyclosporine. |
| Pharmacokinetics: Given i.v. in a series of doses. Daclizumab saturates the Tac subunit of the IL-2 receptor for approximately 120 days post-transplant. |
References: www.rxlist & Katzung's text |
| Drug: Etanercept (Enbrel ®) |
| Drug Class: Monoclonal Antibody / TNF receptor fusion protein |
| Mechanism of Action: A dimer of human IgG1 and the TNF receptor. Etanercept binds to both TNF-alpha and TNF-beta, inhibiting TNF-mediated inflammation. |
| Indications: Adult rheumatoid arthritis, polyarticular course junvenile rhematoid arthritis, psoriatic arthritis. May be used in combination with methotrexate. |
| Pharmacokinetics: Shorter duration of action compared to imfliximab & must begiven s.c. twice a week. |
References: www.rxlist & Katzung's text |
Immunomodulatory
| Drug: Thalidomide (Thalomid ®) |
| Drug Class: Immunomodulatory agent & sedative |
| Mechanism of Action: the immunologic effects of this compound can vary substantially under different conditions, but, may be related to suppression ofexcessive tumor necrosis factor-alpha (TNF-alpha) production and down-modulation of selected cell surface adhesion molecules involved in leukocyte migration. Has antiangiogenic effects as well. |
| Indications: Over 40 different indications including multiple myeloma, management of the skin manifestations of lupus erythematosus & the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). |
| Contraindications: IF THALIDOMIDE IS TAKEN DURING PREGNANCY, IT CAN CAUSE SEVERE BIRTH DEFECTS OR DEATH TO AN UNBORN BABY. |
| Side Effects: Extensive side effects including teratogenesis, peripheral neuropathy, hypothyroidism, thrombosis. |
References: www.rxlist & Katzung's text |
Natural Adjuvants
| Drug: Aldesleukin (Proleukin ®) |
Drug Class: Recombinant Interleukin-2 |
| Mechanism of Action: possesses the biological activities of human native interleukin-2. As such it can cause: a) enhancement of lymphocyte mitogenesis and stimulation of long-term growth of human interleukin-2 dependent cell lines; b) enhancement of lymphocyte cytotoxicity; c) induction of killer cell (lymphokine-activated (LAK) and natural (NK)) activity; and d) induction of interferon-gamma production. |
| Indications:1) the treatment of adults with metastatic renal cell carcinoma (metastatic RCC). 2) for the treatment of adults with metastatic melanoma. |
References: www.rxlist & Katzung's text |
| Drug: Interferon - alpha-2a (Roferon-A ®) |
| Drug Class: Cytokine |
| Mechanism of Action: it is believed that direct antiproliferative action against tumor cells, inhibition of virus replication and modulation of the host immune response play important roles in antitumor and antiviral activity. |
| Indications: the treatment of chronic hepatitis C, hairy cell leukemia, AIDS-related Kaposi's sarcoma, and hepatitis B and C infections. |
References: www.rxlist & Katzung's text |
| Drug: Interferon - beta-1a (Intron-A, Betaseron ®) |
| Drug Class: Cytokine |
| Mechanism of Action: Interferon beta-1b has been shown to possess both antiviral and immunoregulatory activities. The mechanisms by which Betaseron exerts its actions in multiple sclerosis (MS) are not clearly understood. |
| Indications: for use in ambulatory patients with relapsing-remitting multiple sclerosis to reduce the frequency of clinical exacerbations. |
References: www.rxlist & Katzung's text |
| Drug: Interferon - gamma-1b (Actimmune ®) |
| Drug Class: Cytokine |
| Indications: treatment of chronic granulomatous disease |
References: Katzung's text |
Antimetabolite
| Drug: Methotrexate (Rheumatrex ®) |
| Drug Class: Antimetabolite |
| Mechanism of Action: inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of p.r.n. nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of methotrexate. When cellular proliferation in malignant tissues is greater than in most normal tissues, methotrexate may impair malignant growth without irreversible damage to normal tissues. The mechanism of action in rheumatoid arthritis is unknown;it may affect immune function. Clarification of methotrexate's effect on immune activity and its relation to rheumatoid immunopathogenesis await further studies. |
| Indications: neoplastic diseases, psoriasis, rheumatoid arthritis |
| Contraindications: Methotrexate can cause fetal death or teratogenic effects when administered to pregnant women. |
| Side Effects: the most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. |
| Major drug interactions: Leucovorin is indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of methotrexate |
References: www.rxlist & Katzung's text |
Selective COX-2 Inhibitors (coxibs)
| Drug: Celecoxib (Celebrex ®) |
| Drug Class: NSAID (Nonsteroidal Anti-Inflamatory Drug) |
| Mechanism of Action: inhibition of prostaglandin synthesis, primarily via selective inhibition of cyclooxygenase-2 (COX-2) and at therapeutic concentrations in humans, celecoxib is not highly effective in inhibiting the cyclooxygenase-1 (COX-1) isoenzyme. Cox-2 inhibitors have analgesic, antipyretic & anti-inflammatory effects similar to non-selective NSAIDs, but with fewer GI side effects. In general, coxibs have little impact on platelet aggregation (which is mediated by Cox-1) & therefore have minimal cardioprotective effects. However they have been associated with a higher than normal incidence of stroke. |
| Indications: 1) For relief of the signs and symptoms of osteoarthritis, and 2) rheumatoid arthritis in adults. |
| Contraindications: known hypersensitivity to celecoxib. Patients with severe renal insufficiency (Cox-2 is constitutively active in the kidney). |
| Pharmacokinetics: taken orally. Plasma levels of celecoxib occur approximately 3 hrs after an oral dose. Metabolism is primarily mediated via cytochrome P450 2C9. Plasma half life ~11 hrs. |
| Side Effects: Celecoxib is a sulfonamide & may cause skin rashes. The frequency of other side effects is similar to other NSAIDs. |
| Major drug interactions: NSAIDs may diminish the effects of Angiotensin Converting Enzyme (ACE) inhibitors, furosemide and thiazide diuretics. Fluconazole can double celecoxib levels due to inhibition of cyt P450 2C9. Concomitant administration of aspirin with celecoxib may result in an increased rate of GI ulceration or other complications. It interacts occasionally with warfarin (due to cyt P450 C9 metabolism). |
| Note: Celecoxib is not considered to be a good substitute for aspirin for cardiovascular prophylaxis (e.g. because it has minimal effects on platelet function). |
Reference: www.rxlist.com & Katzung's text |
| Drug: Rofecoxib (Vioxx ®) |
| Drug Class: NSAID |
| Mechanism of Action: inhibition of prostaglandin synthesis, primarily via inhibition of cyclooxygenase-2 (COX-2) and at therapeutic concentrations in humans, celecoxib produces relatively little inhibition of the cyclooxygenase-1 (COX-1) isoenzyme. |
| Indications: 1) For relief of the signs and symptoms of osteoarthritis. 2) For the management of acute pain in adults. 3) For the treatment of primary dysmenorrhea. |
| Contraindications: known hypersensitivity to rofecoxib |
| Pharmacokinetics: Rofecoxib is taken orally and is eliminated predominantly by hepatic metabolism with little (< 1%) unchanged drug recovered in the urine, and feces (<14%). Metabolism of rofecoxib is primarily mediated through reduction by cytosolic enzymes. Cytochrome P450 plays a minor role in metabolism of rofecoxib. The effective half- life is ~17 hours. |
| Side Effects: at high doses it is associated with occasional edema and hypertension. Other toxicities are similar to those of other coxibs. |
| Major drug interactions: Same as celecoxib (ACE inhibitors, thiazide diuretics, aspirin). In addition, potentially significant interactions with rifampin, methotrexate and warfarin. Patients receiving these agents with rofecoxib should be appropriately monitored. |
Reference: www.rxlist.com & Katzung's text |
| Drug: Aspirin (Acetylsalicylic acid, ASA) (generic) |
| Drug Class: NSAID |
| Mechanism of Action: Aspirin irreversibly inhibits both isoforms of COX. and inhibits platelet aggregation. Aspirin also interferes with the chemical mediators of the kallikrein system, thus inhibiting granulocyte adherence to damaged vasculature, stabilizing lysosomes, and inhibiting the chemotaxis of PMN leukocytes and macrophages. |
Indications: 1) Anti-inflammatory. Aspirin interferes with the chemical mediators of the kallikrein system, thus inhibiting granulocyte adherence to damaged vasculature, stabilizing lysosomes, and inhibiting the chemotaxis of PMN leukocytes and macrophages. 2) Analgesia. Aspirin is effective in reducing pain of mild to moderate intensity through its effects on inflammation and probably because it inhibits pain stimuli at a subcortical (central) site. It is not effective for severe visceral pain. 3) Antipyretic. Aspirin reduces elevated body temperature (but it has little effect on body temperature in normal healthy patients). This effect is probably mediated by both COX inhibition in the CNS and inhibition of IL-1 (which is released by macrophages during episodes of inflammation). 4) Antiplatelet Effects. Single low doses of aspirin (81 mg daily) produce a slightly prolonged bleeding time, which doubles if administration is continued for a week. The change is due to irreversible inhibition of platelet COX, so that aspirin's antiplatelet effect lasts 8-10 days (the life of the platelet). 5) MI Prophylaxis: Aspirin is indicated to reduce the risk of death and/or nonfatal myocardial infarction in patients with a previous infarction or unstable angina pectoris. 6) Transient Ischemic Attacks: Aspirin is indicated for reducing the risk of recurrent transient ischemic attacks (TIAs) or stroke in men who have transient ischemia of the brain due to fibrin emboli. There is currently no evidence that aspirin is effective in reducing TIAs in women, or is of benefit in the treatment of completed strokes in men or women. |
| Contraindications: hypersensitivity to NSAIDs or history of bleeding disorders, such as GI bleeding or hemophelia. Not recommended during pregnancy, but may be valuable in treating preeclampsia-eclampsia. Children and teenagers should not use this medicine for chicken pox or flu symptoms before a doctor is consulted about Reye's syndrome, a rare but serious illness reported to be associated with aspirin. |
| Pharmacokinetics: Aspirin is rapidly hydrolyzed primarily in the liver to salicylic acid, which is conjugated with glycine (forming salicyluric acid) and glucuronic acid and excreted largely in the urine. As a result of the rapid hydrolysis, plasma concentrations of aspirin are always low and rarely exceed 20 mcg/ml at ordinary therapeutic doses. The peak salicylate level for uncoated aspirin occurs in about 2 hours; however with enteric coated aspirin tablets this is delayed. The plasma half-life for aspirin is approximately 15 minutes; that for salicylate lengthens as the dose increases: Doses of 300 to 650 mg have a half-life of 3.1 to 3.2 hours; with doses of 1 gram, the half-life is increased to 5 hours and with 2 grams it is increased to about 9 hours. Salicylates are excreted mainly by the kidney. Studies in man indicate that salicylate is excreted in the urine as free salicylic acid (10%), salicyluric acid (75%), salicylic phenolic (10%) and acyl (5%) glucuronides and gentisic acid (<1%). |
| Side Effects: Expected side effects are dose-dependent. With therapeutic doses, gastric upset, gastric and duodenal ulcers are the most common side effects. With high doses "salicylism" can occur - vomiting, tinnitus, decreased hearing, vertigo (reversible). Even larger doses cause hyperpnea through a direct effect on the medulla. At toxic doses, respiratory alkalosis followed by metabolic acidosis (salicylate accumulation), respiratory depression, and even cardiotoxicity an glucose intolerance can occur. Overdosage of 200 to 500 mg/kg is in the fatal range. |
| Major drug interactions: Aspirin may contribute to increasing bleeding time by decreasing prothrombin in the plasma. Large doses have a hypoglycemic action that can enhance the effect of oral hypoglycemic drugs and affect the diabetic's insulin requirements. Large doses of aspirin are uricosuric, but smaller amounts may decrease the uricosuric effects of probenecid, sulfinpyrazone and phenylbutazone. Therefore aspirin is contraindicated in the treatment of pain & inflammation associated with gout. |
Reference: www.rxlist.com & Katzung's text |
| Drug: Acetaminophen (generic, Tylenol ®, others) |
| Drug Class: Analgesic, Antipyretic |
| Mechanism of Action: A weak COX-1 and COX-2 inhibitor in peripheral tissues and posesses no significant antiinflammatory effects. Recent evidence suggest that it may inhibit a third enzyme COX-3 in the CNS. It has been proposed that COX-3 may be a splice variant of the COX-1 gene. Acetaminophen produces analgesia by elevation of the pain threshold preipherally, and antipyresis through action on the hypothalamic heat regulating center. |
| Indications: mild to moderate pain such as headache, myalgia, postpartum pain, and other circumstances in which aspirin is also an effective analgesic. It is a prefered drug for the treatment of pain & fever in patients allergic to aspirin, when salicylates are poorly tolerated, in patients with bleeding disorders, history of peptic ulcers, and patients in whom bronchospasm is precipitated by aspirin. Acetaminophen is prefered to aspirin for the treatment of pain/fever in children with viral infections. |
| Pharmacokinetics: Well absorbed orally, with absorption being related to the rate of gastric emptying. Peak blood levels are usually reached in 30-60 mins. Acetaminophen is partially metabolized by hepatic microsomal enzymes and converted to acetaminophen sulfate and glucuronide, which are inactive. Less than 5% is excreted unchanged. A minor but highly active metabolite (N-acetyl-p-benzoquinone) is important in large doses because of its toxicity to both liver and kidney. The half life of acetaminophen is 2-3 hrs. With toxic doses or liver disease, the half-life may be increased two-fold or more. |
| Side Effects: In therapeutic doses, a mild reversible increase in hepatic enzymes may occasionally occure in the absence of jaundice. With larger doses, dizziness, excitement, and disorientation are seen. Ingestion of 15 g of acetaminophen may be fatal, death being caused by severe hepatotoxicity with centrilobular necrosis, sometimes associated with acute renal tubular necrosis. Early symptoms of hepatic damage include: nausea, vomiting, diarrhea & abdominal pain. Toxicity is treated with supportive therapy and N-acetylcysteine to neutralize the toxic metabolites. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion. |
| Notes: Acetaminophen is equal to aspirin in analgesic and antipyretic effectiveness, but differs by lacking anti-inflammatory properties. It also does not affect uric acid levels and lacks platelet-inhibitiing properties. Note that acetaminophen is not a NSAID. |
Reference: www.rxlist.com & Katzung's text |
| Drug: Beclomethasone (QVAR, Vanceril ®) |
| Drug Class: Glucocorticoid (Aerosol) |
| Mechanism of Action: Binds to intracellular glucocorticoid receptors and modulates gene expression. Between 10 to 20% of expressed genes in a cell are regulated by glucocorticoids. The anti-iflammatory effects of glucocorticoids are mainly due to inhibition of phospholipase C. Glucocorticoids have multiple anti-inflammatory effects, inhibiting both inflammatory cells and release of inflammatory mediators. Inhaled beclomethasone probably acts topically at the site of deposition in the bronchial tree after inhalation. Improvement in asthma control following inhalation can occur within 24 hours of beginning treatment in some patients, although maximum benefit may not be achieved for 1 to 2 weeks, or longer. This is associated with the inhibition of lung infiltration by eosinophils. |
| Indications: 1) the maintenance treatment of asthma as prophylactic therapy. 2) indicated for asthma patients who require systemic corticosteroid administration, where adding beclomethasone aerosol may reduce or eliminate the need for the systemic corticosteroids. Beclomethasone is NOT indicated for the relief of acute bronchospasm. |
Reference: www.rxlist.com & Katzung's text |
| Drug: Dexamethasone (generic, Decadron-LA ®) |
| Drug Class: Glucocorticoid, Anti-Inflammatory |
| Mechanism of Action: (see above). Glucocorticoids dramatically reduce the manifestations of inflammation due to their profound effects on the concentration, distribution, and function of peripheral leukocytes and to their suppressive effects on the inflammatory cytokines and chemokines and on other lipid and glucolipid mediators of inflammation. |
| Indications: used for its potent anti-inflammatory effects in disorders of many organ systems. Glucocorticoids cause profound and varied metabolic effects. In addition, they modify the body's immune responses to diverse stimuli. At equipotent anti-inflammatory doses, dexamethasone almost completely lacks the sodium-retaining property of hydrocortisone and closely related derivatives of hydrocortisone. Some specific examples of indications include: rheumatic disorders, arthritis, lupus erythrematosus, bronchial asthma & ulcerative colitis. |
| Contraindications: Systemic fungal infections. Hypersensitivity to this drug. |
| Pharmacokinetics: Available in oral, aerosol and topical forms. Topical corticosteroids can be absorbed from normal intact skin. Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. |
| Side Effects: Sodium retention, fluid retention, steroid myopathy, loss of muscle mass; osteoporosis, aseptic necrosis of femoral and humeral heads, peptic ulcer with possible perforation and hemorrhage, Impaired wound healing. |
| Major drug interactions: |
Reference: www.rxlist.com & Katzung's text |
| Drug: Alprostadil (Caverject, Edex, Muse, Prostin VR Pediatric ®) |
| Drug Class: PGE-1 Prostaglandin |
| Mechanism of Action: Prostaglandin E1 is one of a family of naturally occurring acidic lipids with various pharmacologic effects. Prostaglandins bind to receptors on the cell surface, and pharmacologic specificity is determined by receptor density and receptor type in different tissues. Vasodilation, inhibition of platelet aggregation, and stimulation of intestinal and uterine smooth muscle are among the most notable effects produced by PGE-1. The smooth muscle of the ductus arteriosus is especially sensitive to alprostadil, and alprostadil increases penile cavernous arterial blood flow in vivo. Smooth muscle relaxing effects are mediated by the generation of cAMP. |
| Indications: 1) Prostin VR is indicated for palliative, notdefinitive, therapy to temporarily maintain the patency of the ductus arteriosus until corrective or palliative surgery can be performed in neonates who have congenital heart defects and who depend upon the patent ductus for survival. Such congenital heart defects include pulmonary atresia, pulmonary stenosis, tricuspid atresia, tetralogy of Fallot, interruption of the aortic arch, coarctation of the aorta, or transposition of the great vessels with or without other defects. 2) Caverject is indicated for the treatment of erectile dysfunction due to neurogenic, vasculogenic, psychogenic, or mixed etiology. Intracavernosal Caverject may be a useful adjunct to other diagnostic tests in the diagnosis of erectile dysfunction. |
| Contraindications: Alprostadil should not be used in patients who have a known hypersensitivity to the drug, in patients who have conditions that might predispose them to priapism, such as sickle cell anemia or trait, multiple myeloma, or leukemia, or in patients with anatomical deformation of the penis, such as angulation, cavernosal fibrosis, or Peyronie's disease. |
| Pharmacokinetics: For maintaining the patency of the ductus arteriosus, Alprostadil is given by continuous i.v. infusion. The drug has a rapid pulmonary clearance, requiring continuous infusion. For treatment of erectile dysfunction, alprostadil is administered by injection into the corpora cavernosa. Alprostadil is rapidly metabolized |
| Side Effects: Apnea is experienced by about 10 to 12% of neonates with congenital heart defects treated with Prostin VR Pediatric Sterile Solution. Other side effects include fever (14%) and seizures (4%). A common side effect associaated with Caverject is penile pain after intracavernosal administration (37%). Prolonged erection and priapism are less frequent side effects (<4%). |
Reference: www.rxlist.com & Katzung's text |
| Drug: Dinoprostone (Prostin E2, Prepidil, Cervidil ®) |
| Drug Class: PGE-2 Prostaglandin |
| Mechanism of Action: when administered endocervically it can stimulate the myometrium of the gravid uterus to contract in a manner similar to contractions seen in the term uterus during labor. Dinoprostone also directly affects the collagenase of the cervix, resulting in softening. |
| Indications: for oxytocic use. In the USA, it is approved for inducing abortion in the 2nd trimester of pregnancy, for missed abortion, for benign hydatidiform mole, and for ripening an unfavorable cervix in pregnant women at or near term with a medical or obstetrical need for labor induction. |
| Contraindications: Patients in whom oxytocic drugs are generally contraindicated or where prolonged contractions of the uterus are considered inappropriate (e.g. history of cesarean section, active herpes genitalia, etc.) |
| Pharmacokinetics: PGE2 is completely metabolized in humans. PGE2 is extensively metabolized in the lungs (~95% in first pass), and the resulting metabolites are further metabolized in the liver and kidney. The major route of elimination of the products of PGE2 metabolism is the kidneys. Plasma half life is 2-5 minutes. |
| Major drug interactions: PREPIDIL Gel may augment the activity of other oxytocic agents and their concomitant use is not recommended. For the sequential use of oxytocin following PREPIDIL Gel administration, a dosing interval of 6-12hours is recommended. |
Reference: www.rxlist.com & Katzung's text |
| Drug: Misoprostol (Cytotec ®) |
| Drug Class: PGE-1 synthetic analog |
| Mechanism of Action: Misoprostol has both cytoprotective (low dose) and antisecretory (higher doses inhibit gastric acid secretion) properties. |
| Indications: for the prevention of NSAID-induced gastric (peptic) ulcers in patients at high risk of complications from gastric ulcer |
| Contraindications: contraindicated, because of its abortifacient property, in women who are pregnant. |
| Pharmacokinetics: Misoprostol is extensively and rapidly absorbed after oral administration, and undergoes rapid de-esterification to its free acid, which is responsible for its clinical activity and unlike the parent compound, is detectable in plasma. Half life of 20-40 minutes. |
| Side Effects: diarrhea and abdominal pain. Cytotec has been shown to produce uterine contractions that may endanger pregnancy. |
Reference: www.rxlist.com and Katzung's text |
| Drug: Latonoprost (Xalatan ®) |
| Drug Class: a prostaglandin F2-alpha analogue |
| Mechanism of Action: Latanoprost is a prostanoid, a selective FP receptor agonist that is believed to reduce the intraocular pressure (IOP) by increasing the outflow (or reducing production of) aqueous humor. |
| Indications: for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. |
| Pharmacokinetics: absorbed through the cornea |
Reference: www.rxlist.com |
| Drug: Montelukast (Singulair ®) |
| Drug Class: Leukotriene receptor antagonist |
| Mechanism of Action: a selective and orally active leukotriene receptor antagonist that inhibits the effects of LTD4 at the cysteinyl leukotriene CysLT1 receptor. |
| Indications: prophylaxis and chronic treatment of asthma in adults and pediatric patients 6 years of age and older. |
| Contraindications: history of hypersensitivity |
| Pharmacokinetics:rapidly absorbed following oral administration. Cytochromes P450 3A4 and 2C9 are involved in the metabolism of montelukast. Montelukast and its metabolites are excreted almost exclusively via the bile. Plasma half life is 3-6 hrs. |
| Notes: Leukotrienes are substances that induce numerous biological effects including augmentation of neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability, and smooth muscle contraction. These effects contribute to inflammation, edema, mucus secretion, and bronchoconstriction in the airways of asthmatic patients. Sulfido-peptide leukotrienes (LTC4, LTD4, LTE4, also known as the slow-releasing substances of anaphylaxis) and LTB4, a chemoattractant for neutrophils and eosinophils, can be measured in a number of biological fluids including bronchoalveolar lavage fluid (BALF) from asthmatic patients. |
Reference: www.rxllist.com & Katzung's text |
| Drug: Zafirlukast (Accolate ®) |
| Drug Class: Leukotriene receptor antagonist |
| Mechanism of Action: Synthetic, selective peptide leukotriene receptor antagonist of D4 and E4 (LTD4 and LTE4), components of slow-reacting substance of anaphylaxis (SRSA). |
| Indications: prophylaxis and chronic treatment of asthma in adults and children 5 years of age and older |
| Contraindications: history of hypersensitivity |
| Pharmacokinetics: rapidly absorbed when taken orally. Metabolized by the the cytochrome (CYP2C9) pathway. Mean terminal half life is ~10 hrs. |
| Major drug interactions: increases the plasma concentration & half life of warfarin; concurrent administration of erythromycin decreases zafirlukast plasma levels due to decreased bioavailability |
Reference: www.rxlist.com |
| Drug: Zileuton (Zyflo ®) |
| Drug Class: 5-lipoxygenase Antagonist |
| Mechanism of Action: an orally active and inhibitor of 5-lipoxygenase, the enzyme that catalyzes the formation of leukotrienes (LTB4, LTC4, LTD4, and LTE4) from arachidonic acid. |
| Indications: prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older |
| Contraindications: Active liver disease or transaminase elevations greater than or equal to three times the upper limit of normal, or history of hypersensitivity |
| Pharmacokinetics: Administered orally. Elimination of zileuton is predominantly via metabolism with a mean terminal half-life of 2.5 hours. Metabolized by the cytochrome P450 isoenzymes 1A2, 2C9 and 3A4 (CYP1A2, CYP2C9 and CYP3A4). |
| Side Effects: Dyspepsia |
| Major drug interactions: will increase the plasma levels of theophylline and propranolol and increases their half life if taken concomitantly. (Note: theophylline has a low TI.) |
Reference: www.rxlist.com |
| Drug: Histamine |
| Drug Class: Autacoid (Greek "self-remedy") |
Mechanism of Action: Histamine stimulates H1-H4 receptors. Nervous system: H1 & presynaptic H3 receptors. Cardiovascular: H1 & H2 receptors. Bronchioles: H1. Gastric mucosa: H2 receptors. Triple response of Lewis: mostly H1, some H2 and H3. Postreceptor mechanisms: H1: increased IP3 & DAG (Gq) |
Biological Function: Important mediator of immediate allergic and inflammatory reactions; has an imporant role in gastric acid secretion; and functions as a neurotransmitter and neuromodulator. It may also play a role in chemotaxis of white blood cells. Most tissue histamine is bound in granules (vesicles) in mast cells or basophils. Mast cells have a high density at sites of potential tissue injury - nose, mouth, feet, internal body surfaces, blood vessels. Non-mast cell histamine is found in the brain, where it functions as a neurotransmitter. Histamine is a powerful stimulant of sensory nerve endings, especially those mediating pain & itching (H1 mediated). An additional important site of histamine storage & release is in enterochromaffin-like cells of the fundus of the stomach which release histamine as a secretagogue (H2) to activate acid-producing parietal cells of the mucosa. Histamine, released by mast cells in response to injury, inflammation and allergic responses, causes arteriolar vasodilation, venous constriction in some vascular beds, and increased capillary permeability (by causing endothelial cell contraction). Both H1 and H2 receptors may be involved in the vascular effects of histamine |
Reference: Katzung's text |
| Drug: Betazole |
| Drug Class: H2 agonist |
| Mechanism of Action: A histamine H2 agonist used clinically as a diagnostic aid to test gastric secretory function (e.g. in patients who may have achlorhydria). |
| Drug: Bromopheniramine (Brovex, Dimetane ®) |
| Drug Class: H1 Antagonist (alkylamine subtype) |
| Mechanism of Action: Competitive H1 receptor antagonist |
| Indications: treatment of allergic reactions such as allergic rhinitis, hay fever and urticaria, control of itching related to angioedema |
| Side Effects: slight sedation & anticholinergic side effects |
| Notes: In bronchial asthma, which involves several mediators, H1 antagonists are largely ineffective. |
Reference: Katzung's text |
| Drug: Chlorpheniramine (generic, Chlor-Trimeton ®) |
| Drug Class: H1 Antagonist (alkylamine subtype) |
| Mechanism of Action: Competitive H1 receptor antagonist |
| Indications: (same as bromopheniramine) Provides effective, temporary relief of sneezing, watery and itchy eyes, and runny nose due to hay fever and other upper respiratory allergies. |
| Side Effects: slight sedation & anticholinergic side effects |
| Notes: a common component of OTC "cold" medication |
Reference: www.rxlist.com |
| Drug: Diphenhydramine (generic, Benadryl ®) |
| Drug Class: H1 Antagonist (ethanolamine subtype) |
| Mechanism of Action: Competitive H1 receptor antagonist |
| Indications: 1) Antihistaminic: For allergic conjunctivitis due to foods; mild, uncomplicated allergic skin manifestations of urticaria and angioedema; adjunctive to epinephrine and other standard measures in treatment of anaphylactic reactions - after the acute manifestations have been controlled. 2) Motion sickness: For active and prophylactic treatment of motion sickness. 3) Antiparkinsonism: For parkinsonism (including drug-induced) in the elderly unable to tolerate more potent agents. 4) Local anesthesia: in patients allergic to conventional local anesthetics. 5) Sedation: used as a mild sedative in Tylenol PM ®. |
| Contraindications: should not be used in nursing mothers, newborn or premature infants, or patients with history of drug hypersensitivity to similar antihistamines. |
| Pharmacokinetics: A single oral dose of diphenhydramine HCl is quickly absorbed with maximum activity occurring in approximately one hour. The duration of activity following an average dose of diphenhydramine HCl is from four to six hours. Little, if any, is excreted unchanged in the urine; most appears as the degradation products of metabolic transformation in the liver, which are almost completely excreted within 24 hours. |
| Side Effects: marked sedation; disturbed coordination. Antihistamine overdosage reactions may vary from central nervous system depression to stimulation. Stimulation is particularly likely in children. Atropine-like signs and symptoms, dry mouth; fixed, dilated pupils; flushing, and gastrointestinal symptoms may also occur. |
| Major drug interactions: has additive effects with alcohol and other CNS depressants (hypnotics, sedatives, tranquilizers, etc). MAO inhibitors prolong and intensify the anticholinergic (drying) effects of antihistamines. |
| Note: the salt of diphenhydramine is dimenhydrinate (Dramamine ®), which is commonly used to treat motion sickness. Diphenhydramine is more potent than procaine as a local anesthetic. |
Reference: www.rxlist.com & Katzung's text |
| Drug: Hydroxyzine (generic, Atarax, Vistaril ®) |
| Drug Class: H1 Antagonist (piperazine subtype) |
| Mechanism of Action: 1) H1 competitive receptor antagonist. 2) Bronchodilator activity, and analgesic effects have been demonstrated experimentally and confirmed clinically. 3) An antiemetic effect, both by the apomorphine test and the veriloid test, has been demonstrated. |
| Indications: 1) management of pruritus due to allergic conditions such as chronic urticaria and atopic and contact dermatoses, and in histamine-mediated pruritus. 2) for symptomatic relief of anxiety and tension associated with psychoneurosis and as an adjunct in organic disease states in which anxiety is manifested. |
| Contraindications: contraindicated in early pregnancy (it has been shown to cause fetal abnormalities in rats and mice at doses substantially above the human therapeutic range.) |
| Pharmacokinetics:rapidly absorbed from the gastrointestinal tract and Vistaril's clinical effects are usually noted within 15 to 30 minutes after oral administration. |
| Side Effects: marked sedation, dry mouth |
| Major drug interactions: As a sedative when used as premedication and following general anesthesia, Hydroxyzine may potentiate meperidine (Demerol®) and barbiturates, so their use in pre-anesthetic adjunctive therapy should be modified on an individual basis. |
Reference: www.rxlist.com |
Second Generation H1 Blockers
| Drug: Fexofenadine (Allegra ®) |
| Drug Class: H1 Antagonist (piperidine subtype) |
| Mechanism of Action: antihistamine with selective peripheral H1-receptor antagonist activity. |
| Indications: 1) relief of symptoms associated with seasonal allergic rhinitis in adults and children 6 years of age and older. Symptoms treated effectively include sneezing, rhinorrhea, itchy nose/palate/throat, itchy/watery/red eyes. 2) fexofenadine is indicated for treatment of uncomplicated skin manifestations of chronic idiopathic urticaria in adults and children 6 years of age and older. It significantly reduces pruritus and the number of wheals. |
| Contraindications: known hypersensitivity to fexofenadine |
| Pharmacokinetics: Approximately 5% of fexofenadine gets metabolized. It's half-life is ~14 hours in healthy patients, becoming longer in patients with renal failure. |
| Side Effects: second generation H1 blockers are less lipid soluble, have less complete distribution into the CNS, and have little or no sedative or stimulant actions, and far fewer autonomic effects. |
| Major drug interactions: Despite it's minimal metabolism, co-administration of fexofenadine with ketoconazole or erythromycin can result in increased plasma levels of fexofenadine. Fexofenadine is the metabolite of terfenadine (Seldane ®) which was taken off the market due to it's ability to induce cardiac arrhythmias (torsade de pointes). Fexofenadine does not have the same effect on the heart. |
Reference: www.rxlist.com |
| Drug: Loratadine (Claratin ®) |
| Drug Class: H1 Antagonist (tricyclic subtype) |
| Mechanism of Action: a long-acting tricyclic antihistamine with selective peripheral histamine H1-receptor antagonistic activity |
| Indications: relief of nasal and non-nasal symptoms of seasonal allergic rhinitis and for the treatment of chronic idiopathic urticaria in patients 6 years of age or older. |
| Contraindications: known hypersensitivity |
| Pharmacokinetics: Loratidine is metabolized by cytochrome P450 3A4 (CYP3A4) and, to a lesser extent, by cytochrome P450 2D6 (CYP2D6) to form a metabolite (descarboethoxyloratidine) that is also active. The elimination half-life for in normal adult subjects is 8 hours (range = 3 to 20 hours) for loratadine and 28 hours (range = 8.8 to 92 hours) for descarboethoxyloratadine. |
| Side Effects: few |
| Major drug interactions: cimetidine, erythromycin and ketoconazole can increase loratidine plasma levels, but this is not commonly associated with clinically significant side effects |
Reference: www.rxlist.com |
| Drug: Cromolyn Sodium (generic, Intal, Nasalcrom ®) |
| Drug Class: an inhaled anti-inflammatory agent |
| Mechanism of Action: inhibits both antigen- and exercise-induced asthma, and chronic use (four times daily) slightly reduces the overall level of bronchial reactivity. (Note: cromolyn and nedocromil sodium have no effect on airway smooth muscle tone, and are ineffective in reversing asthmatic bronchospasm.) The cellular mechanism is thought to be an alteration in the function of delayed chloride channels in the cell membrane that inhibits cellular activation in eosinophils & specific mast cells subtypes found in the lung. |
| Indications: Prophylaxis for inhibiting asthma caused by allergens or exercise |
| Contraindications: known hypersensitivity |
| Pharmacokinetics: Intal Inhaler (cromolyn sodium inhalation aerosol) is a metered dose aerosol unit for oral inhalation containing micronized cromolyn sodium |
| Side Effects: throat irritation, bronchospasm |
Reference: www.rxlist.com |
| Drug: Nedocromil (Tilade ®) |
| Drug Class: an inhaled anti-inflammatory agent |
| Pharmacology: essentially identical to cromolyn sodium |
Reference: www.rxlist.com |
| Drug: Cimetidine (generic, Tagamet ®) |
| Drug Class: H2 Antagonist |
| Mechanism of Action: Competitive antagonist at the H2 receptor. (Blocks H2 receptors in parietal cells which supresses basal and meal-stimulated acid secretion in a dose-dependent manner.) Cimetidine also inhibits gastric acid secretion stimulated by food, histamine, pentagastrin, caffeine and insulin. |
| Indications: 1) Short-Term Treatment of Active Duodenal Ulcer; 2) Maintenance Therapy for Duodenal Ulcer Patients at Reduced Dosage after Healing of Active Ulcer; 3) Short-Term Treatment of Active Benign Gastric Ulcer; 4) Erosive Gastroesophageal Reflux Disease (GERD) (Oral Solution Only); 5) Prevention of Upper Gastrointestinal Bleeding in Critically Ill Patients (Injection Only). 6) The Treatment of Pathological Hypersecretory Conditions: (i.e., Zollinger-Ellison Syndrome). |
| Contraindications: known drug hypersensitivity |
| Pharmacokinetics: Undergoes 1st pass hepatic metabolism, resulting in a bioavailability of ~50%. The remainder is secreted into the urine via kidney tubules unchanged. Half life is 2 hrs. Dose reduction is required in patients with moderate to severe renal (and possibly hepatic) insufficiency. In the elderly there is a decline of up to 50% in drug clearance and reduction in Vd. |
| Side Effects: H2 blockers are extremely safe drugs, with side effects in less than 3% of patients (headaches, diarrhea, fatigue). Mental status changes may occur with i.v. administration in elderly. Endocrine effects: cimetidine inhibits the binding of dihydrotestosterone to androgen receptors, inhibits metabolism of estradiol & increases serum prolactin levels. With chronic use may cause gynecomastia or impotence in men & galactorrhea in women. These effects are specific for cimetidine. |
| Major drug interactions: Cimetidine inhibits multiple forms of cytochrome P450 (CYP1A2, CYP2C9, CYP2D6 & CYP3A4). Hence the half-lives of drugs metabolized by these pathways may be prolonged. Examples: warfarin, theophylline, phenytoin, lidocaine, quinidine, propranolol, metoprolol, tricyclic antidepressants, benzodiazepines, calcium channel blockers, sulfonylureas, and ethanol. Ranitidine binds 4-10 times less avidly to cytP450 than cimetidine. H2 blockers also compete with drugs for renal tubular secretion via P-glycoprotein (e.g. procainamide). |
Reference: www.rxlist.com & Katzung's text |
| Drug: Famotidine (generic, Pepcid, Pepcid AC ®) |
| Drug Class: H2 Antagonist |
| Mechanism of Action: same as cimetidine |
| Indications: same as cimetidine |
| Contraindications: known hypersensitivity |
| Pharmacokinetics: Famotidine undergoes minimal first-pass metabolism, but is incompletely absorbed. The bioavailability of oral doses is 40-45%. Famotidine is eliminated by renal (65-70%) and metabolic (30-35%) routes with elimination half-life of 2.5-3.5 hours. There is a close relationship between creatinine clearance values and the elimination half-life of famotidine. |
| Side Effects: headache (5%), dizziness (1%). |
| Major drug interactions: none of clinical significance (unllike cimetidine!) |
Reference: www.rxlist.com |
| Drug: Nizatidine (Axid, Axid AR ®) |
| Drug Class: H2 Antagonist |
| Mechanism of Action: same as cimetidine |
| Indications: same as cimetidine |
| Contraindications: known hypersensitivity |
| Pharmacokinetics: Bioavailability exceeds 70%. More than 90% of an oral dose of nizatidine is excreted in the urine within 12 hours. About 60% of an oral dose is excreted as unchanged drug. Eliminatrion half life is 1-2 hrs. Moderate to severe renal impairment significantly prolongs the half-life and decreases the clearance of nizatidine. |
| Side Effects: few |
| Major drug interactions: none of clinical significance (unllike cimetidine!) |
Reference: www.rxlist.com |
| Drug: Ranitidine (generic, Zantac, Zantac 75 ®) |
| Drug Class: H2 Antagonist |
| Mechanism of Action: same as cimetidine |
| Indications: same as cimetidine |
| Contraindications: known hypersensitivity |
| Pharmacokinetics: 50% absorbed after oral administration. The principal route of excretion is the urine, with approximately 30% of the orally administered dose collected in the urine as unchanged drug in 24 hours. Plasma half life is ~3 hrs in normal patients. Renal impairment prolongs the half-life and decreases the clearance of ranitidine. |
| Side Effects: few |
| Major drug interactions: none of clinical significance (unllike cimetidine!) |
Reference: www.rxlist.com |