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
Will steroids inhibit the early phase response, late phase response, or both of an allergen challenge?
Steroids inhibit the late-phase response but NOT the early phase.
What factors increase clearance of glucocorticoids? What factors decrease clearance?
INCREASED CLEARANCE (decr serum level of GCs):
- carbamazepine, phenobarbital, phenytoin
- rifampin
- antacids (reduce bioavailability)
- hyperthyroidism
- cystic fibrosis
DECREASED CLEARANCE (incr serum level of GCs):
- ketoconazole
- OCPs
- clarithromycin and troleandomycin (for methlyprednisolone)
- protease inhibitors (ritonavir) increase systemic concentrations of inhaled steroids (fluticasone) which causes adrenal suppression and Cushing’s syndrome
What is the mechanism of action for glucocorticoids?
- Free GCs enter cell
- GC binds to glucocorticoid receptor (GR)
- Heat shock proteins dissociate from receptor
- Occupied GRs phosphorylated and translocated into nucleus
Once in nucleus, multiple effects:
-Gene activation via binding to glucocorticoid response element (GRE), leading to upregulation of anti-inflammatory proteins and metabolic effects: osteoporosis, myopathy, growth suppression, cataracts, etc.
-gene repression by binding negative GRE or binding to and/or blocking of transcription factors directly (NFkB).
-induction of transcription factor inhibitors (GILZ, IκBα, etc)
-activation and recruitment of HDACs that prevent DNA unwinding
-destabilize target gene mRNA
What are the anti-inflammatory products increased by glucocorticoids?
- IL-10: only cytokine increased by GCs
- GILZ (glucocorticoid induced leucine zipper): inhibits NFkB and AP-1
- MKP-1 (Map kinase phosphatase-1): inhibits p38 MAP kinase (TNF-alpha, IL-1beta, IL-6, IL-8, GM-CSF)
- IκBα: inhibits NFkB
Which glucocorticoid receptor is associated with steroid resistance that can lead to fatal asthma?
GCβ
- GC beta receptor is a splice variant that lacks a ligand-binding domain, so GR-beta is an inactive form, involved in steroid resistance
- beta can be increased in patients with steroid-resistant asthma and nasal polyps
- What portion of the IgE molecule does omalizumab bind to?
2. What will omalizumab do to eosinophils, mast cells, basophils?
- CH3 domain (Fc portion) of soluble IgE. Typically forms trimers (two IgE to one omalizumab) that are cleared by the reticuloendothelial system. decreases free IgE but increases total IgE (complexes eliminated slowly).
- decrease eosinophils and B lymphocytes
decreased mediator release from basophils and mast cells
decreased FcεRI expression
decreased IL-13
decreased FeNO
Name the molecular target and indication for use of the following:
- mepolizumab
- reslizumab
- benralizumab
- alemtuzumab
- cetuximab
- eculizumab
- efalizumab
- palivizumab
- canakinumab
- abatacept
- alefacept
- secukinumab
- natalizumab
- dupilumab
- rituximab
- mepolizumab: IL-5; eosinophilic asthma
- reslizumab: IL-5; eosinophilic asthma
- benralizumab: IL-5Rα; eosinophilic asthma
- alemtuzumab: CD52; CLL
- cetuximab: epidermal growth factor (EGF); head/neck/colorectal cancers
- eculizumab: complement C5; PNH, aHUS
- efalizumab: CD11a; psoriasis
- palivizumab: RSV fusion protein; prevent RSV bronchiolitis in high risk pediatric patients
- canakinumab: IL-1b; CAPS, JIA
- abatacept: CTLA4-human IgG1 fusion protein that binds to CD80/86 and stops costimulatory signal; RA, JIA
- alefacept: LFA-3-IgG1 Fc fusion protein that binds to CD2; psoriasis
- secukinumab: IL-17A; psoriasis
- natalizumab: α4 integrin; Crohn’s, multiple sclerosis
- dupilumab: IL-4Rα; asthma and eczema
- rituximab: CD20; autoimmune disease
PDE4 is the predominant phosphodiesterase in inflammatory cells, and several PDE4 inhibitors are currently being used to treat various diseases. Can you name PDE4 inhibitors used to treat:
- eczema
- psoriatic arthritis
- severe COPD
- crisaborole
- apremilast
- roflumilast
Describe the mechanisms of action for the following immunosuppressives:
- Methotrexate
- Azathioprine
- Mycophenolate mofetil
- MTX - structural analog of folic acid, inhibits binding of dihydrofolic acid to DHF reductase, leading to lower intracellular folinic acid (inhibits cell replication)
- AZA - converted to 6-mercaptopurine (6-MP), which eventually is converted into nucleotides that inhibit purine nucleotide synthesis and halts replication/proliferation of lymphocytes.
- MMF - inhibits inosine monophosphate dehydrogenase which is an enzyme in purine synthesis. halts proliferation of lymphocytes.
Describe the mechanisms of action for the following immunosuppressives:
- cyclosporin A
- tacrolimus
- sirolimus (rapamycin)
What adverse effects are associated?
1+2: cyclosporin A and tacrolimus first bind to an immunophilin molecule, and this complex then binds to calcineurin. Calmodulin, which normally is turned on by calcium influx, cannot activate the bound calcineurin. Bound calcineurin cannot dephosphorylate and activate NFAT. T cells are particularly susceptible because they have lower number of calcineurin than other cells.
- sirolimus binds an immunophilin, and this complex then inhibits mTOR, which prevents activation of AKT. Sirolimus selectively reduces proliferation of effector T cells while increasing numbers of Tregs and memory T cells.
Adverse effects:
-nephrotoxicity, hypertension, gingival hypertrophy, hypertrichosis
What are two monoclonal antibody drugs that target the alpha chain of the IL-2 receptor? These drugs are approved for prophylaxis of acute rejection of kidney transplants.
Basiliximab (chimeric)
Daclizumab (humanized)
What is the monoclonal antibody drug that targets the p40 subunit shared by IL-12 and IL-23? What disease is this approved to treat?
ustekinumab
Approved to treat plaque psoriasis and Crohn’s disease
- Name an approved JAK inhibitor used to treat rheumatoid arthritis.
- Name an approved JAK inhibitor used to treat polycythemia vera or myelofibrosis.
- tofacitinib - inhibitor of JAK3/JAK1>JAK2
- ruloxitinib - inhibitor of JAK2/JAK1
* JAK2 is greatly involved in signaling for EPO, GM-CSF, and growth hormones
Is COX-1 or COX-2 inhibition associated with undesirable effects of NSAIDs?
How does this inhibition lead to adverse effects?
COX-1 inhibition is associated with undesirable effects because of shunting of arachidonic acid metabolism towards the lipoxygenase pathway, leading to overproduction of leukotrienes.
- Increased LTD4 causes bronchoconstriction and increased vascular permeability.
- Urine LTE4 can be measured to reflect increased production of cysLTs.
- PGE2, an inhibitor of the lipooxygenase pathway, is decreased by COX-1 inhibition
Do patients with low albumin, such as in liver disease, have higher or lower free serum concentration of NSAIDs?
higher free serum concentration of NSAIDs because NSAIDs are tightly bound to albumin. Low albumin leads to more free NSAID in the serum.
Which vaccines contain gelatin as a stabilizer?
MMR, Varicella-zoster, yellow fever, and rabies vaccines
A patient has been on 40mg daily of oral prednisone for the past 3 weeks and wants to get a vaccination. What do you tell her?
Need to wait 1 month after stopping steroids before giving any vaccines.
Vaccines OK to give if <2 weeks of steroid use.
If >20mg/day for 2+ weeks, need to wait 1 month after stopping steroid before getting vaccines.
A patient just started IVIG. When can he get live vaccines?
If IVIG given first, wait 8 to 11 months to give live vaccine.
If live vaccine given first, wait 2 weeks to give IVIG.
Classify the cells/cytokines involved in the following sub classification of Type IV hypersensitivity reactions: Type IVa Type IVb Type IVc Type IVd
Type IVa: Th1 (IFN-gamma). Macrophages.
Type IVb: Th2 (IL-4/13, IL-5). Eosinophils.
Type IVc: CTL (perforin/granzyme). CD4, CD8 cells
Type IVd: T cells and IL-8. PMNs (pustular rash)
Match the following MHC risk markers with related drug allergy:
- HLA-B*5701
- HLA-B*1502
- HLA-DR3
A. carbamazepine
B. abacavir
C. insulin, gold, penicillamine
- B. (HLA-B*5701 and abacavir, reaction in caucasians)
- A. (HLA-B*1502 and carbamazepine in Han chinese, SJS/TEN)
- C. (HLA-DR3 associated with insulin, gold, and penicillamine reactions)
Being sensitized to galactose-alpha-1,3-galactose increases risk for drug-induced anaphylaxis to what drug?
cetuximab, a monoclonal antibody against epidermal growth factor receptor that is used in treatment of colorectal and head/neck cancers.
What drugs can cause immune-induced thrombocytopenia?
- Heparin (specific IgG to heparin-platelet factor 4 forms immune complexes)
- vancomycin
- sulfonamides (bone marrow suppression)
- quinidine
- propylthiouracil
- gold
What drugs are known to cause pulmonary fibrosis/interstitial pneumonitis?
bleomycin
methotrexate
nitrofurantoin
amiodarone
Drug-induced systemic lupus is mediated by what autoantibody? Which drugs are implicated?
antihistone antibodies
procainamide, hydralazine, isoniazid, phenytoin are implicated.
What type of drug will destroy plasma cells?
Proteasome inhibitors like bortezomib.
What type of monoclonal antibody targets CD3 and is used to treat acute transplant rejection?
muromonab-CD3 (OKT3)
