Anti-inflammatory/glucocorticoid Pharmacology Flashcards
H1 - anti histamines
Inverse/neutral agonist against H1 receptor
1st gen: 12 hour H/L; generally sedative
- many first gens can also treat nausea
2nd gen: 12-24 hour H/L; don’t cross into CNS -> non sedative (generally)
Histamine: general info
Vasoactive amine stored in granules of mast cells (tissue specific) and basophils. Responsible for type 1 HSN, i.e. allergic response
Diphenhydramine
1st gen, not a histamine “blocker”: inverse agonist
- sedation, muscarine inhibition (dry mouth)
- crosses into CNS readily so lots of other side effects
2nd gen Anti-histamines
Loratidine: Claritin
Fexofenadine: Allegra
Cetirizine: Zyrtec
- generally don’t cross BBB
Corticosteroids: MOA, indication, administration, contraindications
- Block all known eicosenoid synthesis pathways.
- Anti inflammatory * not effective against acute asthma attacks
- oral administration has highest rate of side effects
- used as maintenance
- contraindicated in: peptic ulcers, HTN, CHF, psychosis, diabetes, osteoporosis and glaucoma
Inhaled corticosteroids
MDI: metered dose inhaler (much more common); DPI: dry powder inhaler
- local SE: dysphonia, thrush and throat irritation
- systemic SE: glaucoma, cataracts, skin change and bruising, infections, psych effect
Fluticasone propionate (Flovent)
Medium potency, medium acting, synthetic corticosteroid
Anti-vasoactive, antipyretic and vasoconstrictive activity
- high lipophilicity
- increased tissue retention
- 14 hour H/L
Budesonide (pulmicort)
Synthetic, non- halogenated form of prednisone
High potency and first past effect, weak mineralocorticoid
2-3.6 hour H/L
Prednisone
Commonly prescribed oral corticosteroid
Metabolized in liver to active form (prodrug)
Hydrocortisone < prednisone < dexamethasone
Adverse side effects of inhaled corticosteroids: short term (2), long term (1)
Short term: hoarseness, oral candidiasis
Long terms: inhibits growth in kids
Adverse side effects of oral corticosteroids: short term and long term
Short term: minimal, behavioral, acute peptic ulcers Long term (14+ days): - adrenal suppression - altered sugar metabolism - infections - skin atrophy - osteoporosis - cataracts
Inhibiting cox enzymes regularly
Can push the eicosenoid pathway towards leukotrienes contributing to asthma
Cox-1
Constitutively produced
Housekeeping, gastric mucosal protection
Maintenance of renal and GI blood flow
Anti-thrombogenic
Cox-2
Inducible enzyme (injury/stress) - inflammation and cancer
NSAIDs: general
Cox inhibitors; commonly used analgesics
- inhibit pro inflammatory cox generated eicosenoids
- also inhibit homeostatic cox generated eicosenoids
Very high albumin binding: underrepresented Vd
Aspirin
Acetylates Serine residues on both cox-1 and 2 (irreversible)
- low dose preferentially inhibits cox-1 (PGE/TXA) reduces platelet activation
- H/L 3-5 hours @ < 300 Mg/day; 1500+ H/L jumps t 15 hrs
SE:
- rapidly absorbed via stomach/upper small bowel (pKa 3.5) and is rapidly hydrolized.
- alkalinization of urine increases excretion
- low dose: GI irritation/bleeding (systemic cause not enteric)
- high dose: salicylism, N/V, hyperventilation, vertigo/tinnitus, metabolic alkalosis
- contraindicated in asthma
Selective COX-2 inhibitors:4
Celecoxib (contraindicated in sulfa allergic and asthma), meloxicam (only partially preferential)* protective against colon polyps
- increased risk of thrombotic event
- hepatotoxic, renal failure
- telomanin
- paroxicam
Key NSAID SE
Non-selective AND COX-2 GI upset/bleed Renal dysfunction Na retention (probably 2dnary to renal dysfunction) Bleeding in general
Non-selective > COX-2 -> GI bleeding
- addition of PPI/H2 receptor blocker can mitigate
COX-2 > no selective -> thrombolytic events.
Leukotrienes
Produced by lipooxengase
- Moderates SRS-A (slow reactive substance of anaphylaxis)
- effectors of asthmatic bronchoconstriction
Leukotriene inhibitors
Montelukast, Zafirlukast, zileuton
- reduce exacerbations
- prevent activity induced, antigen, and aspirin induced bronchoconstriction
Nabumetone
Only prodrug NSAID; ketone that is metabolized to acidic active drug.
- 24 hour H/L
- often requires high dose
- less GI symptoms
- expensive
- can cause pseudoporphyria and photosensitivty
Glucuronidation/sulfination
Two mechanism of conjugating NSAIDS to non-toxic forms
NSAID metabolism/excretion
Mostly unaffected by food intake (bioavailability)
Metabolized mostly by CYP3A/2C (P450 family)
Mostly renal excretion, almost all have slight biliary, excretion/resorption
Naproxen
One of the few NSAIDs that is not a racemic mix
NSAIDS and synovial fluid
Repeated usage results in synovial deposition: short half life drugs are typically present in amounts greater than their H/L would predict. Longer H/L drugs are found in proportion to their H/L
Non-PGE mediated mechs of NSAID activity
- decreased chemotaxis
- down regulation of IL-1 (Hot)
- decreased ROS production
- interference with Ca mediated events
NSAID nephrotoxicity
Pretty much all. Probably a result of interference PGE that regulates blood flow in renal tubules.
General NSAID SE (per katzung)
CNS: HA, tinnitus, dizziness
CV: HTN/edema (rarely MI/CHF)
GI: pain, dysplasia, N/V, bleeding/ulcers
Hematologic: (Rare) Tcytopenia, Npenia possibly aplastic anemia
Hepatic: abnormal liver tests, (rare) liver failure
Skin: rash
Renal: insufficiency, failure, hyperkalemia, proteinuria
Non-acetylated salicylates
Sodium/magnesium salicylate, salicyl salicylate
- all effective, non-platelet inhibiting
- indicated in PTs. with asthma or bleeding conditions
- administered in much higher doses (3-4 g vs 100-200 Mg)
Celecoxib (highly selective) meloxicam (preferentiall selective)
Selective COX-2 inhibitor: (celebate people are more choosey) non-platelet inhibiting, GI SE incidence about 1/2 non selective inhibitors. (Black box: warfarin interaxn)
- non- cardioprotective
- normal renal toxicity
- celecoxib is a sulfonamide; allergies
Diclofenac
Phenylacetic acid derivative
Non-selective COX inhibitor: typically less GI symptoms (especially in combined preparation with omeprazole/misoprostol) (loaf is a solid poo) but renal effects were common in high risk PTs.
- useful in eye surgical cases in gel prep.
Diflunisal
salicylate derivative
Not metabolized to salicylate, enterohepatic glucuronidates it where upon second pass its active moiety is cleaved. (Lun:moon: tide:second pass -> metabolically active)
- especially useful in bone pain (cancer, oral lesions)
- clearance depends on renal function
Etodolac
racemic acetic acid mix
Doesn’t undergo chiral conversion in the body
- 200-400mg TID/QID
- black box: cardiovascular risk, MI and GI bleeding
Flurbiprofen
propanoic acid derivative
Most complex MOA of any NSAID: inhibits COX non-selectively, but also alters TNFa, and NO (flub, how about NO)
- it undergoes extensive hepatic metabolism (fat with a big liver)
- topical ophthalmic formula, HEENT perioperative analgesic, lozenge
- associated with movement deficits (fat and uncoordinated)
Ibuprofen
phenylpropanoic acid derivative
2.4 g = 4 g aspirin (Ib proven: proves itself better, multi tier dosing effect)
- lower incidence of fluid retention relative to indomethacin
Analgesic has lower dose threshold than anti inflammatory effect
- effective at closing a patent ductus arteriosis
- contraindicated in PTs. with nasal polyps, aspirin allergies, and angioedema
- antagonistic action to aspirin
- rarely aseptic meningitis (typically with SLE PTs)
Indomethacin
indole derivative
Non-selective COX inhibitor, and potentially phoslip A/C, neutrophil migration, and B/T cell proliferation
- useable includes, PDA closure, diabetes insipidus, juvenile RA, urticarial vasculitis et al.
- GI symptoms common, but HA (25%) along with cognitive effects including depression, psychosis and hallucination can occur.
- renal papillary necrosis
- probenacid increases its activity by decreasing excretion
Ketoprofen
propanoic acid derivative
Inhibits both COX (non-selectively) and lipoxygenase
- major SE are in GI and CNS
Ketorolac
Analgesic, non-anti inflammatory
- can replace morphine (TORO: bull:strong med:morphine)
- similar common toxicity
Naproxen
napthylpropanoic acid
Only single enatiomer NSAID
- free fraction sig. higher in women but same half life (women use napkins more then men)
- GI bleeding not common, but double that of OTC ibuprofen
- can cause pneumonitis, leukocytoklastic vasculitis
Oxaprozin
propanoic acid derivative
- among subgroup (flurbiprofen, Ibuprofen) it has the longest H/L (50-60 hrs)
(Ox plowed like a pro for 60 hours)
Piroxicam
NON-selective COX inhibitor
At high doses it can inhibit PMN migration, and ROS production
- higher incidence of peptic ulcer and bleeding
- (P-cam: pooper camera can cause bleeding: higher incidence of bleeding, Ox that doesn’t have pro in it)
Sulindac
sulfoxide drug
Reversibly metabolized to active sulfa metabolite. Enterohepatic circulation
- protective agains some colon, breast and prostate cancers
- can be assoc with Stevens-Johnson’s syndrome and cholestatic liver damage
Tolmetin (non-selective COX inhibitor)
Can’t treat gout
Can cause TPP (JD was a tool (toolamitin) for diagnosing dr. Coxs pt with TTP)
DMARDs (only 1st TL)
Disease modifying antirheumatic drugs; immunosuppressive
- abaracept
- azathiopine
- chloroquine (+ hydroxy)
- cyclophosphamide
- cyclosporine
- leflunomide
- methotrexate
- mycophenolate mofetil
Abaracept
MOA: T-cell activation inhibitor (inhibits CD24 binding) (excep T cells)
Kinetics: loading dose @ 0,2,4 weeks then monthly. H/L 13-16 days
Indications: severe RA that has been unresponsive to other DMARDs
ES: increased risk of infection, (IRI) HSN I, possible lymphoma
Azathiopine
MOA: 6-thioguanine inhibits inosinic acid, B/T cell function Ig and IL-2 production
Kinetics: dependent on TPMT activity
Indications: RA, potentially; psoriatic arthritis, reactive arthritis, polymyositis
SE: bone marrow suppression, GID, IRI, potential lymphomas
Chloroquine/hydroxychloroquine
MOA: unknown. Potentially Tcell suppression reducing chemotaxis, stabilization of lysosomal enzymes, inhibition of DNA, RNA and trapping of free radicals
Kinetics: rapidly absorbed, extensively tissue bound in melanin containing tissues (50% free) H/L up to 45 days.
Indications: RA but not very effective. Useful for trt of skin manifestations
SE: ocular toxicity at high doses (hydroxy more potent), dyspnea, N/V, abd. Pain. Nightmares
Cyclophosphamide
MOA: phosphoramide mustard cross links DNA-> B/Tcell suppression 30-40%.
Kinetics: Katzung ch54.
Indications: RA ORALLY. SLE and other RA diseases
SE: Katzung ch 54
Cyclosporine
MOA: alters gene txn, and suppresses IL-1 and IL-2, inhibits macs -T cell interaxn. B cell function is also effected.
Kinetics: absorption is incomplete and erratic. Grapefruit juice increases absorption up to 62%.
Indications: RA, retards bony erosions
SE: leukopenia, tcytopenia, anemia, cardiotoxicity, sterility, bladder cancer (rare)
Leflunomide
A77-1726 inhibits dihydroorate dehydrogenase -> decreased RNucleotide synthesis, decreased IL-10, NF-kB (roughly equal efficacy to methotrexate)
Kinetics: completely absorbed with a 19 day H/L, can enter enterohepatic circulation. Cholestyramine can increase H/L by 50%.
Indications: RA, stopping bony erosions, synergistic with methotrexate
SE: diarrhea, liver enzyme elevation, mild alopecia, weight gain and BP increase.
Methotrexate
First line DMARD for RA
MOA: at lower (sub chemo levels) AICAR transformylase and thymadylate synthetase is inhibited -> increases AMP -> converted to Adenosine which is a potent anti inflammatory agent. Also effects chemotaxis
Kinetics: 70% absorbed after oral admin. H/L 6-9 hours (up to 24 hours. Renal excretion = 70%, biliary excretion = 30%
Indications: RA with boney erosions, lots of other AA itis conditions
SE: Nausea, mucosal ulcers common. Leukopenia, anemia, hepatotoxicity, lung HSN possible. NOT for preggers.
NSAID SE: CNS- 3
Tinnitus, dizziness, HA
NSAID SE: Cardiovascular - 5
Fluid retention, HTN, edema, Myocardial infarction (rare), CHF (rare)
NSAID SE: gastrointestinal - 5
Abdominal pain, dysplasia, nausea, vomiting, ulcers/bleeding (rare)
NSAID SE: hematologic - 3
Thrombocytopenia (rare), neutropenia (rare), aplastic anemia (rare)
NSAID SE: hepatic - 2
Increased liver enzymes, liver failure (rare)
NSAID SE: pulmonary - 1
Asthma
NSAID SE: skin - 2
Rashes, pruritis
NSAID SE: renal - 4
Renal insufficiency, renal failure, hyperkalemia, proteinuria
CYP2A/CYP3C
Primary metabolism of NSAIDs
ROSCaILCh
Non-PG mediated effect if NSAIDs
- ROS burst modification
- Ca med processes down reg
- IL-1 altar ion (anti pyrogenic)
- chemotaxis alteration
Probenacid
Increases the efficacy of some NSAIDs by inhibiting clearance
ductus arteriosis closure
Ibuprofen and indomethacin
iBID
Na NSAIDs
NAproxen and NAbumetone
- both can result in pseudoporphyria
- bums with bad vision: photosensitivty in NAbumetone use
- proximal limb: vasculitis with naproxen use
Betamethasone
Lung development in premature (34 weeks) infants. Betamethasone is preferred because maternal proteins don’t bind it as much so higher dose gets to baby
(beta for Bebes)
Isoproterenol
Potent broncodilator
- dangerous due to its ability to induce arrythmias
- IsoproTERRORnol….cause it can kill you
Rol, Nol, but
Albuterol, terbutaline, metaproterenol, pirbuterol
- B2 selective agonists
- most RS mixes that are inhaled
- terbutaline is available IM
- 3-4 hour activation time
Salmeterol, formotorol (formoterol)
Long acting B2 selective agonists (12hours)
- (keeps your motor running)
Roflumilast
Methylxanthine trt for COPD
Caffeine, theophylline, theobromine
Decrease inflammation by decreasing PDEs -> increased cAMP
- PDE4 has been implicated in inflammatory cells
N-acetylcystine
Antidote to acetaminophen OD. Original dose dependent
No acetylation
Cyclosporine
Anti-necrotic process drug: retards swelling of mitos by inhibiting mito trans pores.
(Spore:Pores)
