Pharmacology Flashcards
How does fingolimod work and what is it used to treat?
sphingosine-1-phosphate receptor modulator, approved for treatment of multiple sclerosis. In vivo, fingolimod becomes phosphorylated and mimics S1P as an agonist at S1P receptors. Chronic activation of S1P receptors leads to inactivation and downregulation of the receptor so that T-cells stay put within lymph nodes. Also, likely enhances junctional contacts in endothelium thereby closing egress ports.
Colchicine is used as prophylaxis of familial mediterranean fever (FMF). What are the main side effects of colchicine?
GI distress including pain and bleeding
Bone marrow suppression (rare)
Treatment of TRAPS involves first-line anti-IL1 therapy and avoiding anti-TNF mAb’s like infliximab and adalimumab as they can paradoxically cause flares.
What are the anti-IL1 therapies used as first-line treatment of TRAPS?
There is also a TNF blocking agent that can be used as 2nd line therapy, what is it and why is it different from the above anti-TNF mAb’s?
Anti-IL6 therapy is 3rd line–what is the name of the drug?
Anti-IL1 therapies:
- canakinumab - mAb that neutralizes IL1-beta
- anakinra - recomb IL-1 receptor antagonist
TNF blockade:
-Etanercept: fusion of TNFR2 and IgG Fc; acts as a TNF blocker
Anti-IL6:
-tocilizumab: IL-6 receptor antagonist
*Colchicine does not work for TRAPS, unlike FMF where colchicine is a major prophylactic therapy.
Anakinra, canakinumab, and rilonacept are all anti-IL1 therapies. How are their targets/mechanism of action different?
canakinumab - human mAb that neutralizes IL1-beta
anakinra - recombinant and slightly modified form of IL-1 receptor antagonist protein
rilonacept (IL-1 trap) - ligand-binding domains of the extracellular portions of the human interleukin-1 receptor component (IL-1R1) and IL-1 receptor accessory protein (IL-1RAcP) linked in-line to the fragment-crystallizable portion (Fc region) of human IgG1. binds and neutralizes IL1-beta
Would the following conditioning regimen be considered myeloablative, reduced intensity, minimal intensity, or no conditioning?
Busulfan+cyclophosphamide+ATG
Myeloablative
Nicknamed “BuCyATG”
What are the drugs ivacaftor, lumacaftor-ivacaftor, and tezacaftor-ivacaftor used to treat?
CF Variants
Class I: complete absence of CFTR
Class II: CFTR trafficking to cellular locus abnormal (delta-F508)
Class III: Impaired channel activity in response to ATP
Class IV: Reduced ion flow and channel opening
Class V: Reduce quantity of functional CFTR
Ivacaftor for G551D and 32 other gating mutations (Class III)
Lumacaftor-ivacaftor for F508del - for pts homozygous for F508del (delta F508, Class II)
Tezacaftor-ivacaftor for F508del-homozygotes or heterozygotes that have residual function mutation (Class III or IV)
Which antihistamines can be used in the setting of renal failure? How about liver failure?
Renal failure: use loratadine or first generation antihistamines (all hepatic clearance only)
Liver failure: use fexofenadine (renal clearance only)
What are the potential adverse effects of H1 antihistamines?
- sedation: anti-H1 receptor effect
- dry mouth: anticholinergic effect
- urinary retention: anticholinergic effect
- increased appetite (cyproheptadine): antiserotonergic
- hypotension and reflex tachycardia (promethazine): anti-alpha-adrenergic effect
- prolonged QT: ion channel effect
What is the mechanism of action of beta-agonists?
Bind to G protein-coupled receptors and activate adenylyl cyclase, resulting in increased cAMP, which activates protein kinase A, leading to phosphorylation and smooth muscle relaxation.
β2 receptors are found on lung and inflammatory cells
How does salmeterol cause a longer duration of action than albuterol?
How does formoterol cause a longer duration of action than albuterol?
Salmeterol “exo site” hypothesis: a long hydrocarbon chain with a hinge-Oxygen (which is very hydrophobic and therefor very lipophilic) is added to albuterol. The lipophilic portion binds to a site outside of the active site (“exo-site”) forcing the albuterol molecule portion to bounce up and down on the active site. Long duration; slow onset compared to formoterol.
Formoterol is intermediate lipophilic, sits in membrane and intermittently released to activate beta2 receptor. Long duration; rapid onset.
Formoterol is a FULL AGONIST so can get a dose-dependent effect.
Albuterol and Salmeterol are PARTIAL AGONISTS so no dose-dependent effect.
With repeated beta-agonist exposure over weeks, there is downregulation of beta2 receptors causing desensitization. Does this cause a decrease in 1) degree of bronchodilation, 2) duration of bronchodilation, or 3) both?
What can reverse beta2 receptor downregulation?
There is a decrease in DURATION of bronchodilation, but no effect on the degree of bronchodilation.
Systemic steroids can reverse beta2 receptor downregulation and upregulate beta2 receptor expression.
- Which leukotriene receptor is involved in bronchoconstriction?
- What is the order of affinity for this receptor amongst the cysteinyl leukotrienes?
- Do leukotriene antagonists attenuate early phase, late phase, or both phases of the allergic response?
- CysLT1
- LTD4 > LTC4 > LTE4
- both
Which leukotriene modifier blocks the formation of cysteinyl leukotrienes (LTD4, LTC4, LTE4) as well as LTB4?
What drugs have increased serum levels when coadministered with this drug?
What is a major side effect that warrants monitoring every 3 months?
Zileuton (5-LO inhibitor).
- Inhibits cytochrome CYP1A2: decreased clearance (increased serum levels) of theophylline, warfarin, and propanolol
- can cause elevated transaminases so ALT should be monitored every 3 months.
- Avoid in patients with history of liver disease or substantial alcohol consumption.
Why can’t we use atropine as an anticholinergic bronchodilator?
hallucinogenic (crosses blood-brain barrier), with numerous adverse effects (dry mouth, urinary retention) that limits its use for airway disease.
Ipratropium can cause paradoxical bronchoconstriction as a side effect. Why does tiotropium cause less paradoxical bronchoconstriction than ipratropium?
Ipratropium blocks M2 and M3 muscarinic receptors. M3 is the primary mediator of smooth muscle contraction in airways. M2 is inhibitory on parasympathetic nerves, and blocking M2 receptors too much leads to net increased acetylcholine release from vagus, causing bronchoconstriction.
Tiotropium also block M2 and M3, but dissociates from M2 faster than M3, and dissociates from M3 100 times more slowly than ipratropium, so longer duration of action and less paradoxical bronchoconstriction.
What is the mechanism of action for theophylline? What serum level commonly causes adverse effects?
- weak and nonselective inhibitor of phosphodiesterase (PDE) resulting in elevated cAMP/cGMP, resulting in bronchodilation and anti-inflammatory effects. Can also increase HDAC2 activity (suppresses inflammatory cytokine gene expression)
- VERY NARROW THERAPEUTIC WINDOW: 5-15mg/L. Adverse effects common at >20mg/L
- adenosine antagonism responsible for toxic effects at high concentrations (seizures, arrhythmias)
What factors increase clearance of theophylline? What factors decrease clearance?
INCREASED CLEARANCE (decr serum level of theo):
- Carbamazepine, phenobarbital, phenytoin
- rifampin
- ethanol
- smoking tobacco/marijuana
- high protien/low carb diet
- younger children
DECREASED CLEARANCE (incr serum level of theo): Macrolides cimetidine (but NOT ranitidine) ciprofloxacin verapamil zileuton allopurinol CHF liver disease viral infection high carb diet older age
