- reversible analgesic/fever reducer (similar effects to Aspirin). Inhibits COX-PG synthesis in brain. Not anti-inflammatory. Can be safely used if allergies to aspirin.
- OD causes HEPATOTOXICITY in 4 days.
- Acetaminophen specifically works against both Prostaglandin H2 synthases.
- Metabolized by CYP-450-2E1.
Aspirin: (Salacylic Acid)
- irreversible COX inhibitor. Anti-fever/anti-platelet/analgesic/anti-inflammatory.
- Also down regulates leukocyte adhesion molecules.
- Used in treatment of Rheumatoid arthritis, Rheumatic Fever, & prophylactically for platelet aggregation prevention.
- Adverse Effects: can cause gastric bleeding (ulcers) from COX-1 inhibition & can disable immune system (contraindicated in young people for this purpose.)
- PG’s needed for Diuretic action, so Aspirin contraindicated when in use.
- Don’t use aspirin while pregnant or if you have Gout. 200mg/kg = toxic dose.
- OD causes metabolic/respiratory acidosis. Can cause internal bleeding w/ warfarin/heparin/ethanol. Hinders effects of insulin, ACE inhibitors, & Probenecid (Gout).
- Anti-mitotic drug (binds tubulin); reduces inflammation by PMN’s in joints.
- Used sparingly in to treat GOUT acutely b/c of its severe toxic effects.
- anti-inflammatory drug. Links TNF receptor to IgG FC portion.
- IgG prevents inflammation from occurring.
- ADVERSE EFFECTS: serious infections can occur by inhibiting inflammatory process.
- reversible analgesic/fever reducer/anti-inflammatory.
- Works equally on COX1 &2. 2-hr half life.
- Highest pain relief score (above aspirin + codeine)
- highly ANTI-INFLAMMATORY (not routine use); some analgesia related to inflammation. HIGH TOXICITY:
- gastric bleeding as well as esophageal/stomach perforations.
- injectable NSAID. Potent COX-1 inhibitor--lots of GI problems.
- Use for patients who can’t take oral meds.
- selective Xanthine Oxidase inhibitor.
- Well tolerated in Gout patients who can’t use Allopurinol.
- Metabolically inactivated, so no need for adjustment for the renally impaired.
- Gout treatment. Decreases Uric Acid by blocking tubular reabsorption.
- But only works at sub-therapeutic levels??? Aspirin negatively interacts with it.
- highly TERATOGENIC drug.
- Reduces levels of TNF-a. (anti-inflammatory).
- Treat Mult. Myeloma/AI skin diseas.
- alkylating drug that slows/stops cell growth.
- Acts by cross-linking DNA/RNA/proteins in S-phase.
- Is a Prodrug. Used as a chemotherapy drug for lymphomas & leukemias.
- Also used to treat AI diseases (Lupus nephritis).
- ADVERSE EFFECTS: bone marrow suppression (Trombocytopenia & Neutropenia). Bladder Cancer.
- immunosuppressive drug. Inhibits dephosphorylation of Calcineurin (secondary messenger needed for T-cell DIFFENTIATION);
- prevents secretion of IL-2 . Lack of T-cell proliferation affects B-cells.
- Used in treating Grafts & autoimmune diseases.
- ADVERSE EFFECTS: Nephrotoxicity & Recurrent infections.
- immunosuppressive drug. Treats inflammatory disease.
- Inhibits Dihydrofolate-Reductase (folate metabolism)-required for DNA synthesis-
- greater toxicity on rapidly proliferating cells, so inhibits proliferation of lymphocytes.
- Used as a CHEMO drug—affective against cancer & Rheumatoid A.
- Adverse: immune-suppressive/Teratogen.
- immunosuppressive PROdrug.
- Selectively inhibits lymphocyte purine synthesis.
- Often used in treatment of Lupus Nephritis.
- Adverse = (increased infection)
- immunosuppressive anti-CD3 MAB (CD3= TCR receptor complex)—targets T-cells.
- Rho(D) immune Globulin : injectable anti-D IgG AB’s; attaches to and kills Rh+ RBC’s in maternal blood.
- Prevents mother from mounting immune response to Rh+ RBC’s & forming her own anti-D+ Ab’s.
- prevents Erythroblastosis Fatalis.
Immunosuppressive drug. Binds FK (needed for intracellular T & B cell PROLIFERATION signal from IL-2)
- Immunosuppressive drug. Binds to FKBP(responsible for dephosphorylating Calcineurin)-same as cyclosporine
- ---used to Treat ATOPIC DERMATITIS (Exzema)
synthetic IL-2… upregulates activity of NK & T cells. used to treat metastatic Renal Cell Carcinoma
immunosuppressive: blocks LFA/CD2 costimulation signal on T-cells—APOPTOSIS. Used to treat Psoriasis & T-cell Lymphomas
Requirements for Glucocorticoid anti-inflammatory effects:
- C-11 Hydroxyl group,
- C-20-21 side chain,
- C-4,5 dbl bond
General Glucocorticoid method of action via intracellular receptor interaction:
- -Directly by: TRANSREPRESSION (decreased transcription)of NF-kB & AP-1 genes (pro-inflammatory secondary messengers)
- -Indirectly: upregulating ANNEXINS, lipocortin, that in turn down-regulates PLA2, COX, & NO expression
- -also upregulates IkB-----another inhibitor of NF-kB transcription
- -reduce tissue histamine levels
Physiologic Effects caused by Glucocorticoids:
- -increased gluconeogenesis & decreased glucose use in peripheral tissues (vital organ survival).
- -protein & bone degradation
- -high amounts can affects salt/water balance (bind to mineralocorticoid receptors)
- *Suppress Inflammatory/Immune responses
- -increase RBC’s, but Decrease WBC’s
- -delays wound healing (Fibroblast proliferation decreased)
Common Uses for Glucocorticoids:
- -prevent Septic Shock & Fetal Distress Syndrome (long acting cross placenta better)
- -Arthritis & organ transplants
- -skin diseases (ATOPIC DERMATITIS---EXZEMA) & allergies
Side Effects & Contraindications:
- -Hypertension & Hyperglycemia (insulin resistance)
- -myopathay & osteoporosis
- -increases opportunistic infections & Glaucoma
- *contraindications: Growth retardation, Peptic Ulcers, Osteoporosis
- To Minimize Side-Effects:
- -Timing (w/circadian rhythm), pulse dosing, use other drugs adjunctively, regional administration, use of short/medium acting steroids, or alternate days of treatment.
- short acting interacts w/ glucocorticoid receptors (affinity for Mineralocorticoid receptors, but converted to
- Cortisone which can be considered inactive metabolite or prodrug); formed in the adrenal cortex.
- Pro-drug of cortisol (lacks 11-OH group)-activated in body. short acting anti-inflammatory (usually topical).
- Higher efficacy than cortisol (inc. gluco-receptor affinity, dec. mineralo-receptor affinity, longer duration of action, longer half-life, etc.)
- short acting anti-inflammatory (usually topical for asthma and intranasally). (10% bioavailability!)
- Addition of 16,17-butylidenbid[oxy] moiety increases absorption (lipophilic)
- short acting anti-inflammatory (intranassally & Topically). (0% Bioavailability!)
- Adding lipophilic side chain (proprianate) enhances efficacy especially when applied topically and is used for asthma and dermatology.
Medium-acting steroid. 1-2 double bond slows liver metabolism increasing glucocorticoid effect
Medium-acting steroid. Only differs from prednisolone by 6-methyl
- Prodrug of Prednisolone. (11-OH missing).
- Converted in body to active (replaces 11 ketone with 11-OH).
- Differs from cortisol only by 1-2 double bond
- Medium-acting steroid. Differs from prednisolone with 9-flouride.
- 16-17 acetonide analog used topically for dermatological disorders
- long acting steroid. 9-Chloride and 16-methyl.
- Requires esterase cleavage of side-chain for activation.
- Diproprianate beclamethasone can be used in asthma treatment.
- only difference from beclomethasone is 9-flouride.
- Diproprianate betamethasone used for dermatology.
- long acting steroid. Requires esterase cleavage of side-chain for activation.
- Can be used in asthma treatment. Same structure as betamethasone?
marketed PGE2 for uterine contraction
combo of antiprogestins & PGE2 (Dinoprostone); causes abortion.
- PGE1 used to treat Erectile Dysfunction; also used to maintain Patent Ductus Arteriosus
PGI2 used to treat hypertension (vasodilatory effects)
5-LOX inhibitor; treats asthma (Leukotrienes D4 & C4 mainly responsible for asthma effects)
- analogue of PGE1; used to treat/prevent gastric ulcers (from NSAIDS);
- PG’s protect stomach
- (PGE1) relaxes smooth muscle.
- Maintains the ductus arterosus patent in some neonates awaiting cardiac surgery.
- This counteracts the decrease in PGE2 levels that lead to closure.
- In delayed closure of the ductus arteriosus, COX inhibitors are often used to inhibit synthesis of PGE2 and close the ductus.
- Also used in the treatment of erectile dysfunction.
- (PGE1 derivative) is a cytoprotective prostaglandin used in preventing peptic ulcers in those taking dose NSAID therapy.
- Also used in combination with mifepristone (RU486) for terminating early pregnancies.
- (PGE2) PGE2 and PGF2α are used in obstetrics to induce labor.
- Theoretically, PGE2 and PGF2α should be superior to oxytocin for inducing labor in women with preeclampsia-eclampsia
- or cardiac and renal diseases because they have no antidiuretic effect.
- In addition, PGE2 has natriuretic effects.
- In cases of intrauterine fetal death, the prostaglandins alone or with oxytocin seem to cause delivery effectively.
- These prostaglandins appear to soften the cervix by increasing proteoglycan content and
- changing the biophysical properties of collagen.
- (PGI2) : prostacyclin used to treat pulmonary hypertension;
- decreases bronchial and vascular tone; decreases platelet aggregation in dialysis machines.
Topically active PGF2α derivatives used in ophthalmology to treat open angle glaucoma.
- (leukotriene receptor antagonists): potent bronchodilators used to treat asthma;
- Leukotrienes (LTC4, LTD4 and LTE4) are heavily involved in asthmatic constriction;
- montelukast does not inhibit CYPs 2C9 and 3A4 so would not affect elimination of other drugs as much as Zafirlukast.
(5-LOX inhibitor): Inhibits leukotriene synthesis; used in asthma treatment; not as effective as the leukotriene receptor antagonists.
- *can cross placenta
- *young eliminate more rapidly than old
- *H1 = constriction (large vessels/bronchioles); H2 = dilation (precapillary arterioles)
- General H1 antagonists: block broncho/vasoconstriction, edema, flare, itch, & rhinitis associated w/ H1 receptors
- -hypotensive effect still not controlled b/c H2 dilation involvement
- *1st Generation = sedating (lipophilic); 2nd Generation = non-sedating normally; (Ethanol can compound sedative effect)
- *H1 antagonists not indicated for common cold, but do relieve symptoms (rhinitis, conjunctivitis); “drying” effect.
- *H1 antagonist Side Effects: sedation, GI problems, dry mouth/cough/dysuria (anti-Ach-drying),tachycardia, allergic
- 1st Generation is an Ethanolamine; lipophilic, so can cross BBB---SEDATIVE effects.
- Also inhibits sodium channels at high doses (anesthetic.)
- 1st Generation an Ethanolamine; lipophilic, so crosses BBB (sedative).
- Also antagonizes the muscarinic Ach receptors (treats vertigo/motion sickness)
1st Generation an Alkylamine; known to have side effects of CNS stimulation.
1st Generation anti-cholinergic (muscarinic); ANTI-EMESIS. Anesthetic @ high doses (Na channels).
2nd gen. H1 antagonist.
2nd Generation excreted in feces. (Piperadine)
2nd Generation prodrug that is activated by p450 to desloratidine (Piperadine)
2nd Generation already active form of Loratidine (Claritin)---(Piperadine)
2nd gen H1 antagonist. Piperazine family
2nd Generation inhibits mast cell degranulation by stabilizing their membrane. Prophylactic for asthma.
has same effect as cromolyn sodium