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infliximab
- DMARD - anti-TNFα agent
- humanized ab to TNFα that binds TNFα
- prevents interaction with its receptor, reduces circulating and localized levels of TNFα
- application: inflammatory disease involving TNFα
- - rheumatoid arthritis (combination with methotrexate) - elevated TNFα in joints
- - Crohn's disease (combination with azathioprine) - elevated TNFα in stool
- PARENTERAL administration
- complications: increased freq. of infections (upper resp., urinary)
-
adalimumab
- DMARD - anti-TNFα agent
- humanized ab to TNFα that binds TNFα
- prevents interaction with its receptor, reduces circulating and localized levels of TNFα
- application: inflammatory disease involving TNFα
- - rheumatoid arthritis (combination with methotrexate) - elevated TNFα in joints
- - Crohn's disease (combination with azathioprine) - elevated TNFα in stool
- PARENTERAL administration
- complications: increased freq. of infections (upper resp., urinary)
-
etanercept
- DMARD - anti-TNFα agent
- fusion protein containing the ligand binding domain of the TNFα receptor and Fc domain of human IgG
- prevents interaction with its receptor, reduces circulating and localized levels of TNFα
- application: inflammatory disease involving TNFα
- - rheumatoid arthritis (combination with methotrexate) - elevated TNFα in joints
- - Crohn's disease (combination with azathioprine) - elevated TNFα in stool
- PARENTERAL administration
- complications: increased freq. of infections (upper resp., urinary)
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anakinra
- DMARD - anti IL1 agent
- competitive IL-1 receptor antagonist (IL-1Ra analog)
- treats RA, possibly other inflammatory diseases
- short half-life, daily injections req'd
- complications: increased susceptibility to infection
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tofacitinib
- general Jak kinase inhibitor
- approved for RA as second line therapy for those failing methotrexate
- ORAL
- mechanism: inhibits all activity of cytokines req'd for adaptive immunity (IL-2, IL-4)
- inhibits all activities for some inflammatory cytokines (IL-6)
- therapeutic doses chosen to produce incomplete Jak inhibition (current 5mg bid, higher doses produce potent immunosuppression and adverse effects)
- adverse effects: anemia, neutropenia, general myelosuppression, inc. risk of infection (herpes zoster), long term safety unknown
- effect: comparable to anti TNFα agents in reducing active disease in RA
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prednisone
- combined immunosuppressive and anti-inflammatory effects (focus on anti-inflammatory)
- affects gene txn as ligands for glucocorticoid receptors
- reduces expression of inflammatory cytokines (IL-1, TNFα) which reduces propagation and amplification of inflammatory rxns
- reduced expression of chemokine reduces recruitment of new leukocytes into sites of inflammation
- inc. expression of annexing inhibits PLA2 activity and reduces AA production
- - reduced prostanoid synthesis
- - reduced leukotriene synthesis
- reduced expression of COX=2 leads to reduced prostanoid production in response to inflammatory stimuli
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histamine
- synthesized in most tissue and stored in complex with sulfated polysaccharides
- - can be displaced by certain amines (morphine) which causes inappropriate release
- degraded via diamine oxidase
- non-inflammatory effects: NT in CNS stimulates wakefulness and promotes emesis, particularly in response to motion; GI tract H2 histamine receptors increase acid production
- Inflammatory effects: IgE antibody rxn promotes histamine release from mast cells in type 1 hypersensitivity rxns (allergy, anaphylaxis), via H1 type receptors
- - constrict vascular endothelial cells to increase fluid permeability = tissue edema
- - NO release from endothelial cells via histamine causes vascular relaxation and dilation = hypotension and anaphylaxis (significant histamine release)
- - causes sensations of itching and release of vasodilators at distal nerve branches = wheal-and-flare response to hives (urticaria)
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cromolyn and nedocromil
- histamine release inhibitors
- poorly soluble salts with poor bioavailability
- used in asthma therapy - topically absorbed (inhaled powder aerosol)
- inhibits degranulation of mast cells, possibly assoc. with the inhibition of Ca2+ channels
- inhibits Cl- channels which may contribute to reduced nerve activity and inhibition of cough
-
diphenhydramine and dimenhydrinate
- first generation antihistamine
- H1 antagonist
- used for allergic rhinitis and urticaria, and motion sickness and emesis
- adverse effects: sedation (additive effect with other CNS depressives)
- - anticholinergic effects: dry mouth, urinary retention, tachycardia
- - adrenoreceptor blockade: orthostatic hypotension
- - serotonin receptor blockade: inc. appetite
- - local anesthesia: block sodium channels
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cyclizine and promethazine
- first generation antihistamine
- H1 antagonist
- used for allergic rhinitis and urticaria, and motion sickness and emesis
- adverse effects: sedation (additive effect with other CNS depressives)
- - anticholinergic effects: dry mouth, urinary retention, tachycardia
- - adrenoreceptor blockade: orthostatic hypotension
- - serotonin receptor blockade: inc. appetite
- - local anesthesia: block sodium channels
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loratadine
- 2nd generation antihistamine: high selectivity for H1 sites, few anti-cholinergic side effects
- used for allergic rhinitis and urticaria, and motion sickness and emesis
- sedation effects are reduced because of poor penetration to CNS
-
cetirizine
- 2nd generation antihistamine: high selectivity for H1 sites, few anti-cholinergic side effects
- used for allergic rhinitis and urticaria, and motion sickness and emesis
- sedation effects are reduced because of poor penetration to CNS
-
fexofenadine
- 2nd generation antihistamine: high selectivity for H1 sites, few anti-cholinergic side effects
- used for allergic rhinitis and urticaria, and motion sickness and emesis
- sedation effects are reduced because of poor penetration to CNS
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ketorolac and indomethacin
- NSAID - cox 1/2 inhibitor
- highest selectivity for COX1 (ketorolac = 395, indomethacin = 10)
- see notes
-
naproxen and ibuprofen
- NSAID - cox 1/2 inhibitor
- see notes
-
diclofenac and etodolac
- NSAID - cox 1/2 inhibitor
- see notes
-
meloxicam
- NSAID - cox 1/2 inhibitor
- see notes
-
misoprostol
- PGE1 analog
- protects against COX-1 inhibition
- blocks NSAID-induced ulcers but not other anti-inflammatory effects
-
acetaminophen
- relatively non-selective Cox1/2 inhibitor with reduced activity in the presence of peroxides at sites of inflammation
- lack anti-inflammatory activity (not an NSAID)
- no significant effect on platelets, CV, and GI system
- analgesic and antipyretic effects (equiv to aspirin)
- well tolerated, hepatotoxicity with overdose or combination with other hepatotoxic agents (alcohol)
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celecoxib (Celebrex)
- COX 2 selective NSAID
- selectivity ratio significantly less than 0.1 (10-20x more selective for COX2)
- preserves COX1 activity
- anti-inflammatory, antipyretic, analgesic, renal toxicity
- mainly used to treat osteoarthritis and rheumatoid arthritis
- tolerance: reduced GI effects in patients not taking aspirin
- Adverse effects: increase incidence of HTN, MI, stroke (long-term use)
- remains available despite evidence of risk
-
zileuton
- leukotriene synthesis inhibitor (inhibits 5-lipoxygenase, which leads to inhibition of the synthesis of LTB4 and LTD4 in mast cells and eosinophils)
- varied effectiveness, but can be used as long-term maintenance therapy for asthma (oral)
- assoc with liver toxicity
- inhibits: cytochrome P450 1A2, 2C9, 3A4 (decreases metabolism of other drugs)
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zafirlukast and montelukast
- leukotriene receptor antagonist
- long-term maintenance therapy for asthma (oral)
- allows reduction in corticosteroid dosage
- LTD4 receptor antagonists reduce bronchoconstriction and edema assoc. with inflammatory response
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