therapeutic modalities, steroids, non steroids, demard

Question 1

What are some side effects of opioid treatment?

Answer 1

Acute side effects of opioids I.V. include the respiratory depression, acute anaphylactoid reaction-erythema, urticaria, angioedema via mast cell degranulation, IgE mediated allergy. Overdose-hypothermia, miotic pupils, respiratory depression-frequency, volume, somnolent, bradycardia/tachycardia, orthostatic hypotension, decreased bowel sounds, urinary retention, ureteric and biliary colic, muscle rigidity, rhabdomyolysis, sedation, euphoria. dizziness, flushing myoclonus, confusion, hallucinations, delirium, headache.
Chronic use for pain relief (opioid use disorder) induces dry mouth, miosis, nausea and vomiting, constipation, itching, drowsiness. Problems with traffic accidents, incidental falls, and failure to return to work increase.
Prolonged treatment in men results in testosterone deficiency and osteoporosis.
Abdominal pain often severe, chronic or recurring, is usually significantly improved following withdrawal of opioids.

Question 2

What are the major side effects of methotrexate treatment?

Answer 2

Adverse effects of methotrexate include bone marrow toxicity (leukopenia, thrombocytopenia, anemia), cirrhosis and fibrosis, opportunistic infections (PCP, CMV, herpes zoster, fungal, mycobacterial) will hypersensitivity pneumonitis, organizing pneumonia, noncardiogenic pulmonary edema, pulmonary fibrosis, asthma-restrictive airway disease, arthritis, oligospermia, teratogenicity, and malignancy.

Question 3

What are some commonly used antidepressants taken by patients with rheumatic disorders?

Answer 3

Commonly used serotonin reuptake inhibitors include sertraline (Zoloft 200), citalopram (Celexa 40), fluoxetine (Prozac, C17H18F3NO 80), escitalopram (Lexapro 20), duloxetine (Cymbalta 120). Common tricyclic antidepressants are amitriptyline (Elavil, C20H23N 300 ).Trazodone (Desyrel, C19H22ClN5O 600) is a serotonin antagonist as well as a reuptake inhibitor, nortriptyline (Pamelor) 75 pain 150 dep, bupropion (Wellbutrin C13H18ClN0 1 benzene ring 200 bid) is a norepinephrine – dopamine reuptake inhibitor, and venlafaxine (Effexor) is a serotonin norepinephrine reuptake inhibitor.

Question 4

What approved medications are available to increase bone density?

Answer 4

Medications used to treat osteoporosis include the biphosphonates alendronate ( Fosamax 5,10 mg qd 70 qw), risedronate (Actonel 5 qd 35 qw 150 qm), ibandronate (Boniva 150 qm, 3mg iv q3m), zoledronic acid ( Reclast 5mg iv ?q2y), selective estrogen receptor modulators such as raloxifene (Evista 60 mg qd), monoclonal antibodies against osteoclast receptor RANKL –(Receptor Activator of Nuclear factor Kappa B Ligand (TNFSF11)) denosumab (Prolia 60 mg q6m), parathyroid hormone - teriparatide (Forteo 20 mcg qd).

Question 5

How well does splenectomy work in treating thrombocytopenia?

Answer 5

Splenectomy for thrombocytopenia works in a 80-90% whereas rituximab is effective in 50-60%. Younger patients respond more often, but there is no age where response is impossible. The risk of overwhelming infection post splenectomy is 0.7 per 1000 patient-years.

Question 6

How damaging is sunlight in patients taking Thiopurines?

Answer 6

Thiopurines (azathioprine) photosensitize human skin to UVA radiation and increased risk for skin cancer, requiring protection against UVA and lifelong dermatological surveillance. Odds ratio 5.0 for nonmelanoma and 12 for melanoma in Caucasians.

Question 7

How long does it take to develop tolerance to opioids?

Answer 7

Tolerance to opioids usually develops within three weeks of daily use. Less time with higher doses. Euphoria is the first effect to decrease. No tolerance develops to miotic defects or constipation.

Question 8

What are common signs of opiate withdrawal?

Answer 8

Common signs after 3-4 hours include drug craving, anxiety, fear of withdrawal. After 8-14 hours mydriasis, yawning, increased bowel sounds, dysphoria, restlessness, rhinorrhea, lacrimation,and after 3-4 days piloerection, myalgias, arthralgias, nausea, vomiting, abdominal cramping, tachycardia, and hypertension.
Symptoms are severe following abrupt heroin withdrawal, less with methadone or buprenorphine.

Question 9

What are the differences between Dilantin, Neurontin, and Lyrica?

Answer 9

Phenytoin (Dilantin) is an anticonvulsant C15H12N202-2 benzene rings, with an effect on sodium channels, 300-600 mg average daily dose.
Gabapentin (Neurontin) is an anticonvulsant, analgesic drug C9H17NO2-cyclohexane ring, that may act on voltage-gated calcium channels. 900-1800 mg/day.
Pregabalin (Lyrica) C8H17NO2-Hexanoic acid, is an anticonvulsant, designed to be more potent than gabapentin on calcium channels. >600 mg/day not more effective pain control.
Lyrica inhibits the release of glutamate, norepinephrine, substance P, and calcitonin gene related peptide

Question 10

What are some of the side effects of trazodone treatment?

Answer 10

Trazodone (max dose 600 mg) may cause postural hypotension, prolonged QT interval, and ventricular tachycardia especially early post MI. 1/6000 men develop priapism early during the course of treatment. It is metabolized by the CYP3A4 liver enzyme often inhibited by grapefruit juice.

Question 11

What is the frequency of methotrexate induced pulmonary hypersensitivity and what are the risk factors?

Answer 11

Methotrexate induced lung disease occurs in 1-8% of patients within the first year after starting treatment for immune or malignant problems. Risk factors include age>60, rheumatoid pulmonary involvement, previous DMARD treatment, hypoalbuminemia, diabetes mellitus, daily treatment, abnormal PFT’s, prolonged blood levels as with ascites-3rd space effect. Dose relationship not nearly as strong as for bleomycin.
Activating NFkB related to folate pathway may be stimulated more than adenosine production.

Question 12

How many different forms of vitamin K are there?

Answer 12

Vitamin K1, phylloquinone (aliphatic side chain) is synthesized in plants for photosynthesis, . Animals convert this to vit K2 menaquinone (isoprenoid side chain MK1 to 7). Phylonadione  (Mephyton) is a stereoisomer of K1  available by injection 1 mg/0.5 mL or as 5 mg tablets-100 tabs $2446.
Vit K2 (MK7) sold as supplements are available 100 mcg/tab 100 for $8.

Question 13

What is the metabolic role of vitamin K?

Answer 13

Oxidized vitamin K is known as KO and the reduced form as KH2 via vitamin K epoxide reductase complex 1. KH2 is the active form used in Gla (Gamma carboxygLutAmatic domain) ((COOH)2C-C-C(NH2)-COOH=C6H9NO6, carboxy glutamic acid) synthesis via gamma-glutamyl carboxylase. 2 carboxylic residues bind calcium. Gla domain formation is blocked by warfarin inhibition of KH2 formation.
vitamin K is necessary activation of factors VII, IX, X, and prothrombin. These proteins thereby gain affinity for negatively charged phospholipids on the surface of platelets and promote coaggulation.
Vitamin K2 as MK-4 prevents osteoporosis via osteocalcin and vitamin D but not K1 or MK-7.

Question 14

How does coagulopathy from dietary K deficiency differ from that induced by warfarin?

Answer 14

Vitamin K deficiency resulting from malnutrition results in high titer abnormal clotting factors that do not bind to phospholipid. Warfarin induces a mix of normal and abnormal clotting factors so that the risks of hemorrhage can be rapidly reversed.

Question 15

how many types of voltage dependant calcium channels are there?

Answer 15

All voltage-dependent calcium channels share similar subunits; alpha 1 forming the central pore and alpha-2-delta, beta 1-4, and gamma forming supportive structures that modulate gating. There are 5 functional types:

1) DHP (1, 4-dihydropyridine ~Nifedipine) sensitive-L-type, L or Long lasting, in skeletal muscle, smooth muscle, osteoblasts, ventricular myocytes, dendrites in dendritic spines of cortical neurons,
2) P-type in Purkinje neurons,
3) N-type throughout the brain and peripheral nerves,
4) R-type in cerebellar granular cells and other neurons, and
5) T-type in neurons with pacemaker activity, and osteocytes.

Question 16

How do you manage patients who develop methotrexate lung hypersensitivity yet fail to respond to stopping methotrexate?

Answer 16

Stopping methotrexate is the major therapy although prednisone at 1 mg per kilogram may help in severe cases without extensive lung damage. Further evaluation in patients who fail to respond to discontinuation, should exclude bacterial, fungal, and viral infections-pneumocystis, Cryptococcus, cytomegalovirus, or be zoster, nocardia, mycobacteria, as well as lymphangitic tumor and lymphoproliferative disease.

Question 17

Where are the signs and symptoms of methotrexate induced lung disease?

Answer 17

Pneumonitis may be mild to severe; fever-76%, chills, malaise, nonproductive cough-81%, dyspnea-82%, chest pain, rales, cyanosis. Lung pathology includes eosinophilia, lymphocytic infiltrates, fibrosis, and poorly organized granulomas. Chest x-ray shows diffuse infiltrates, more in the lower lobes, and CT scans may show patchy or diffuse ground glass changes and/or honeycombing, reticular opacities.

Question 18

What PDE4 inhibitor is approved to treat psoriatic arthritis?

Answer 18

Apremilast (Otezia) is a PDE4 inhibitor approved for use in psoriatic arthritis. Side effects include depression, weight loss <2%, diarrhea , headache, nausea, nasal congestion, sore throat, URI, vomiting, and stomach pain. No significant laboratory changes were noted.
Starting dose is 10 mg on the first day in b.i.d. for one day and 10 mg a.m. and 20 mg p.m. for one day then 20 mg in the a.m. and 30 mg p.m. then 30 mg b.i.d. thereafter. If real failure then 30 mg daily. $2250/mo

Question 19

How does rapamycin work?

Answer 19

Rapamycin arrests G1 to S phase transition in fungi and T lymphocytes by inhibiting mTORC1 serine/threonine kinase-binds FKBP12, and immune cell phosphorylation of AKT, S6K1, and 4EBP1.

Question 20

What immunosuppressive agents are bacterial macrolides - large macocyclic lactone ring?

Answer 20

-Ciclosporin (Gengaf, Neoral discovered 1969 Norway, 1972 immunosuppressive, approved 1983).
-sirolimus (Rapamune,discovered 1975 from Streptomyces on the island of Rapa Nui, as anti-fungal, approved immunosuppressant 1999).
-tacrolimus (Prograf discovered 1984 Japan, immunosuppressive approved 1994 liver transplantation ).
Ciclosporin binds to cyclophillin (prolyl isomerase) and inhibits binding to calcineurin .
Tacrolimus (Prograf) binds FKBP12 (prolyl isomerase, FK506) thus inhibits binding to calcineurin.
Rapamycin binds FKBP12 and then MTORC1 rather than calcineurin.

Question 21

What risk develops with aggressive CTLA-4 receptor blocking?

Answer 21

Ipilimumab (MDX 010) blocks the CTLA-4 T cell receptor (activated by CD80/86, and is approved for use to improve immunotherapy against melanoma.
CTLA-4 (Cytotoxic T Lymphocyte Associated protein 4, CD152) on cytotoxic T cells is activated by CD80/86 and the suppression permits tumor growth. Ipilimumab turns this off.
CD28 is the initial T cell membrane protein to bind CD80/86 which provides the second stimulate to activate T cells.
PD-L1 (Programed Death-Ligand 1, CD274) is activated by CD80/86, and inhibits CD8 cytotoxic T cells.

Question 22

What ion channels does ranolazine affect to relieve angina pectoris and neuropathy pain?

Answer 22

Ranolazine (Ranexa) affects the trans cellular late sodium current via the sodium-dependent calcium channels-NAV 1.7 1.8. It protects against angina pectoris and may help neuropathic pain.

Question 23

How is methotrexate pulmonary hypersensitivity prevented and diagnosed?

Answer 23

When starting methotrexate a baseline chest x-ray and pulmonary function tests help to exclude premorbid conditions that contraindicate its use. chest x-ray and CT examination are usually done with bronchoscopy reserved for progressive disease in spite of stopping therapy, or suspicion of infection or malignant complications. Pulmonary function tests with diffusion capacity (restrictive, DLCO<70%) help to identify severe cases where bronchoscopy and biopsy would be helpful.

Question 24

How does thalidomide work?

Answer 24

Thalidomide, lemalidomide and pamalidomide complexes with and destroys cereblon (442 aa) which binds to calcium-activated potassium channel (KCNMA1). Forms complexes that ubiquinate growth factors and other proteins.
Transcription factor inhibition results in decreased synthesis of IRF4 (interferon regulatory factor 4) and myc resulting in multiple myeloma toxicity. Ubiquination effects result in increased IL-2 and decreased TNF, oxidative stress, and inhibition of angiogenesis.
Genetic defects result in mental retardation.
Cereblon form an E3 ubiquitin complex with multiple proteins, and is heavily expressed in cerebrum.

Question 25

What is the dose of various monoclonal antibodies used to treat RA?

Answer 25

etanercept (Enbrel 50 mg SubQ qwk or 25 mg twice weekly),
adalimumab (Humira 40 mg SubQ q2wk, 40 mg q1wk in not taking MTX),
certolizumab (Cimza 400 mg SubQ at 0,2,4 wks then 200 mg q2wk,or 400 every 4wk, use with or without MTX),
golimumab (Simponi 50 mg SubQ q4wk; 2 mg/kg I.V. 0 wk then in 2 wk then every 8 wks, use with MTX),
tocilizumab (Actemra anti IL-6) 4 mg/kg I.V. q4wk up to 8 mg/kg. SubQ 162 mg every 2 wk if < 100 kg, q wk if > 100 kg, use with MTX ),

Question 26

What is the best way to reduce prednisone that is currently taken at over 40 mg daily and is no longer needed?

Answer 26

Prednisone is reduced by 10 mg per week until the dose is 40 mg per day.
After one week on 40 mg per day the prednisone dose should be tapered by 5 mg each week until the patient is on 20 mg per day.
After one week of 20 mg per day the dosage is reduced by 2.5 mg per day per week until taking 10 mg per day.
After two weeks on 10 mg per day the dosage is reduced by 1 mg every two weeks until the dosage is at 5 mg per day.
After two weeks of 5 mg per day the dosage should be reduced by 1 mg per month and then discontinued after one month at 1 mg per day.

Question 27

List antirheumatic therapy by mechanism of action.

Answer 27

Antirheumatic treatment may be divided by the target they modify which exist in;

1) extracellular fluid compartment:
a) inhibiting active factors
- TNF

Question 28

Tofacitinib requires dose adjustment for what conditions, and side effects ?

Answer 28

Tofacitinib (Xeljanz) 5 mg bid requires dosage adjustment for CYP3A4 inhibitors (rifampin, ketoconazole fluconazole), renal failure, hepatic failure, lymphopenia, anemia < 8 g Hgb,
Side effects include infection risk>10%, serious infection 2%, UTI 2%, URI 5%, nasopharyngitis 4%, headache 4%, diarrhea 4%, hypertension 2%, increased ALT 1%.
Age <60, increased PR interval, Asian ancestry increases overall risk.

Question 29

What is the usual intravenous dose of cyclophosphamide for treatment of glomerulonephritis?

Answer 29

Cyclophosphamide at 0.5-1 g/m2 should be adjusted by 0.25 g/M 2 if the previous dose decreased the total white cell count by brings the 1500. Genetic status-African-American or Hispanic receive higher doses at the 1 g range for 6 doses every month and Caucasian every 2 weeks at 0.5 g for 6 doses.

Question 30

What commonly used drugs in patients with rheumatic disease require a dosage adjustment for real failure?

Answer 30

Commonly prescribed drugs in rheumatology that require dosage change due to renal disease include anticoagulants-low molecular weight heparin’s
cardiac drugs-sotalol, atenolol
diuretics-avoid potassium sparing diuretics
opioids-morphing, codeine
psychotropic/anticonvulsant-gabapentin, lithium, levetiracetam,
hypoglycemic drugs metformin
drugs for gout-allopurinol, colchicine
DEMARD-methotrexate
Pregabalin (Lyrica) needs one half the usual dose with creatinine clearances

Question 31

What patients are most likely to develop hepatotoxicity during the first seven months of methotrexate treatment?

Answer 31

Patients with obesity, untreated high cholesterol, elevated pre-methotrexate enzymes, use of a biologic agent, and no folic acid supplementation.

Question 32

What are some paradoxical effects of anti-TNF therapy?

Answer 32

Paradoxical effects of anti-TNF agents include posriasiform skin reactions, uveitis, and granulomatous disease-sarcoid, Crohn’s.

Question 33

How does bisacodyl work?

Answer 33

Bisacodyl works by increasing PGE2 secretion by colonic macrophages and also decreases AQP3 in the colon. Increased secretion with decreased reabsorption of fluid accounts for the increased bowel activity. Stimulated colonic smooth muscle not small intestine.
Indomethacin inhibits this process.

Question 34

How does senna work?

Answer 34

Senna ( Cassia senna) is an anthraquinone derivative results in potentiation of cardiac glycosides, antiarrhythmic drugs, and calcium channel blockers. It stimulates colonic fluid secretion as well as peristalsis. Ex-Lax, sennosides.

Question 35

What medication is approved for use in constipation due to irritable bowel?

Answer 35

lubiprostone (Amitiza) is derived from prostaglandin E1 and works by activating CLC-2 chloride channels. Increased secretion softens stool and increases motility.
CLCN2 is the gene for chloride channel protein 2. Mutations are associated with leukoencephalopathy and idiopathic generalized epilepsy.
Comes in 8 and 24 mcg tabs (both $369/60 tabs), start with 8 qd then up to 24 bid if necessary.

Question 36

What is the best antihypertensive agent to use in someone with gout?

Answer 36

Losartan (Cozaar) a non peptide angiotensin 2 receptor antagonist, should be used in gouty patients as it does not increase the uric acid level. 50 to 100 daily.

Question 37

What might oral biphosphonates do for macular degeneration?

Answer 37

Oral biphosphonates (alendronate) might reduce neovascularization in age-related macular degeneration after six months. They are proinflammatory and anti angiogenic.

Question 38

What are some side effects of inhibiting vascular endothelial growth factor?

Answer 38

Bevacizumab side effects include hypertension and bleeding. Nasal septum perforation and renal thrombotic microangiography has been reported. The risk increases for perforations of the nose, stomach, and intestines. Necrotizing fasciitis complicates treatment of colon cancer.

Question 39

What medications work as phosphodiesterase inhibitors?

Answer 39

Phosphodiesterase inhibitors are classified as
nonselective-caffeine, aminophyline, pentoxifyline
PDE1 selective inhibitors vinpocetine
PDE2 oxindole
PDE3 citostazol (heart failure)
PDE4 roflumilast COPD
PDE5 sildenafil, dipyridamole
PDE7 quinazoline-anti-inflammatory and neuro protective
PDE10 papaverine, works in isolated cerebral cortex areas.

Question 40

What monoclonal antibody inhibits IL-17 ?

Answer 40

ustekinumab (Stelera) inhibits IL-17, a proinflammatory cytokine that is released by T helper cells similar to interferon gamma, and acts synergistically with TNF and IL-1 to produce a delayed inflammatory response.

Question 41

What medications are effective in treating rheumatoid arthritis?

Answer 41

Effective treatment include NSAID’s, glucocorticoids, sulfasalazine, hydroxychloroquine (Plaquenil), methotrexate (Trexal) , azathioprine (Imuran), leflunomide (Arava), cyclophosphamide, mycophenolate mofetil (CellCept), mycophenolic acid (Myfortic), cyclosporine (Neoral), etanercept (Enbrel), adalimumab (Humira), infliximab (Remicade), golimumab (Simponi), certolizumab pegol (Gimzia), abatacept (Orencia), tocilizumab (Actemra), rituximab (Rituxan), or ustekinumab (Stelera).

Question 42

What is the mechanism of action of abatacept?

Answer 42

CTLA-4 Ig suppresses T cell activation by interfering with CD80/86-CD28 co stimulation by interfering with recognition of CD28.
CD 28 on T cells has multiple intracellular binding motifs attracting SH2 (PI3K, Grb2 and Gads), and SH3 contain proteins resulting in activation of NF-kB and IL-2.

Question 43

What is the dose of various biologics used to inhibit IL-1?

Answer 43

IL1-ra (Anakinra 1-2 mg/kg SubQ daily), infliximab (Remicaide 3mg/kg at 0, 2, 6wk then 3-10 mg/kg every 4-8 weeks, use with MTX),
Canakinumab (Ilaris) at 180 mg every eight weeks if > 40 Kg.

Question 44

What are the benefits and risks of bone marrow transplant in SLE?

Answer 44

Bone marrow transplant in SLE before 1990 had a mortality rate of 12% remission rate of 66% with relapse in 33%.
By 2013 complete remission rate of 28%, and one year and 17% at three years relapse rate is 23%, mortality of 6% by 7 yr all unrelated.

Question 45

What is the starting dose of azathioprine in treatment of lupus?

Answer 45

azathioprine 0.5 mg/kg/d in two divided doses increased by 0.5 at two weekly intervals to maintenance dose of 2 mg/kg/day

Question 46

What are some of the side effects of glucocorticoid treatment?

Answer 46

Side effects of glucocorticoid treatment:
-characteristic early and unavoidable
insomnia, emotional stability, enhanced appetite or weight gain or both
-common in patients with underlying risk factors or other drug toxicities:
hypertension, diabetes mellitus, peptic ulcer disease, acne vulgaris.
-Anticipated with sustained an intense treatment:
Cushingoid habitas, hypothalamic-pituitary-adrenals suppression, infection diathesis, osteonecrosis, myopathy, impaired wound healing.
-insidious and delayed-dependent on cumulative dose
osteoporosis, skin atrophy, cataracts, atherosclerosis, growth retardation, fatty liver.
-Rare and unpredictable:
psychosis, pseudo tumor cerebri, glaucoma, epidural lipomatosis, pancreatitis.

Question 47

How do glucocorticoids induce immunosuppression?

Answer 47

Glucocorticoids suppress immunity through multiple pathways including:

1) inhibition of nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-kB), the major inflammatory transcription factor.
2) suppressing cell mediated immunity by inhibiting genes that code for IL-1, IL-2, IL-3, IL-4,, IL-5, IL-6, IL-8, and IFN gamma. T cell proliferation is thus reduced.
3) induces apoptosis of both T and B cells.
4) immunity is suppressed through reduction of IL-2 and IL-2 receptors on B cells
5) down regulates expression of Fc receptors on macrophages, decreases phagocytosis.
6) increases annexin V (lipocortin-1) which suppresses phosphatase A-2 blocking eicosanoid production and inhibiting leukocyte epithelial adhesion, emigration, chemotaxis, phagocytosis, and inspiratory burst. Prostaglandins and leukotrienes are suppressed

Question 48

When does steroid myopathy develop, and how is it diagnosed and treated?

Answer 48

Steroid myopathy develops in some patients taking over 40-60 mg of prednisone daily presenting with gradual onset of painless weakness in the legs then the arms after 2 to 4 weeks. In patients with brain tumor taking dexamethasone, 2/3 developed symptoms in the third to fourth month. The diagnosis initially is one of exclusion as muscle enzymes and EMG are usually normal. A firm diagnosis is made when steroids are stopped and strength returns within 3 to 4 weeks. Patients with underlying myositis or taking neuromuscular agents to help with artificial ventilation (critical illness myopathy) take longer to recover.

Question 49

What do the following monoclonals do?ustekinumab 
otelixizumab 
zanolimumab is a monoclonal human antibody against C4 in trials as HuMax-C4 in rheumatoid arthritis, psoriasis, melanoma and T-cell lymphoma. pub med=lymphoma only after 2009
daclizmab, IL-13 
librikizumab, IL-5 
mepolizumab, reslizumab, benralizumab 
eculizumab
toralizumab
blisibimod

Answer 49

ustekinumab binds to the p-40 subunit of IL-12 and 1L23 inhibiting both.
otelixizumab is a human monoclonal antibody directed against the epsilon chain of C-3. Trials in juvenile diabetes prevention arm progress.
zanolimumab is a monoclonal human antibody against C4 in trials as HuMax-C4 in rheumatoid arthritis, psoriasis, melanoma and T-cell lymphoma. pub med=lymphoma only after 2009
IL-2 daclizmab IL-2
librikizumab, , IL-13
mepolizumab, reslizumab, benralizumab IL-5 eculizumab C5a
toralizumab
blisibimod is a fusion protein containing four BAFF binding domains fused to an Fc portion of a human antibody. Blisibimod binds to BAFF inhibiting BAFF receptors resulting in decreasing B cell survival and proliferation. Disease activity is reduced in SLE and rheumatoid arthritis.

Question 50

What is the relative rate of AST/ELT elevation in rheumatoid patients taking methotrexate and/or leflunomide?

Answer 50

AST/ALT elevations >1 x normal occur in 14% of control patients with RA, 17% in those taking leflunomide, 22% in those on methotrexate, and 31% in those taking both. Corona trial
There are no clinical case reports of severe liver toxicity in patients taking leflunomide. Only 1 case report of SJ syndrome with elevated enzymes that resolved. 1 report from india of 65 cases of lethal drug induced hepatitis mentioned 75% mortality rate with leflunomide but too rare to list among causes where most due to anti TB medication.

Question 51

What is the mechanism of action of azathioprine?

Answer 51

Azathioprine (purine with S at top of pyrimidine ring >C-S-ring) is hydrolyzed to 6-mercaptopurine >C=S, metabolized by HGPRT (hypoxanthine-guanine phosphoribosyl transferase) to Timp (Thioinosine monophosphate). Then inosine-5’-monophosphate dehydrogenase (IMPD) and GMPS (guanine monophosphate synthetase) and several kinases produce 6-TGN (6-thioguanosine nucleotide) which is incorporated into DNA and methylated. Mismatch repair than induces translation errors-cellular dysfunction.
Methylation of TIMP produces 6-methylthioinosinate (MTIMP). If Both Timp and MTIMP inhibit glutamine-5-phosphoribosylpyrophosphate amidotransferase, the first step in purine synthesis.
6-mercaptopurine is inactivated by a TPMT into 6-MeMP (6-methyl mercaptopurine) and via XO (Xanthine oxidase) into 6-TUA (6-thiouric acid) both of which are inactive.
If c=S were c-NH2, 6-MP would be adenine.
If c=S were c=O, 6-MP would be inosine.
If c=S were c=O + H2N, 6-MP would be guanine.

Question 52

What is the mechanism of action of methotrexate?

Answer 52

The cytosolic target of methotrexate is the enzyme 5-aminoimidizole-4-carboxamide ribonucleotide transformylase (ATIC). Inhibition increases AICAR (5-aminoimidizole -4-carboxamide ribonucleotide, C9H13N5O4) levels which inhibit AMP deaminase 1 and adenosine deaminase leading to increased adenosine (C10H13N5O4) levels. Extracellular release of adenosine then stimulates adenosine receptors (ADORA1-A2A- A2B) resulting in inhibition of antigen presentation, costimulation, immune cell trafficking and proliferation, cytokine production, and cytotoxicity.

Question 53

What is the mechanism of action of mycophenylate derivatives?

Answer 53

Mycophenylate is a reversible inhibitor of inosine monophosphate dehydrogenase which controls the rate of guanine monophosphate synthesis necessary for the proliferation of B and T cells. Other cells can use salvage pathways.

Question 54

What is the mechanism of action of cyclophosphamide?

Answer 54

Cyclophosphamide works by adding an alkyl group to quanidine bases within DNA forming intrastrand and extrastrand cross-links.
Cyclophosphamide is converted to phosphoramide mustard and the bladder toxic acrolein. Aldolase dehydrogenase converts phosphoramide mustard to inactive carboxycyclophosphamideso that cells with high levels such as bone marrow stem cells, liver, and intestinal epithelium are somewhat protected.
Cyclophosphamide should be decreased as renal function decreases, 2 mg/kg down to 1.2 at 50 ml/min and 0.8 if on dialysis.

Question 55

How does Calcineurin inhibition result in immunosuppression?

Answer 55

Peptidylprolyl isomerase cytoplasmic enzymes convert cis proline protein structures to trans configuration as a post translational modification which results in faster protein folding. Peptidylprolyl isomerase proteins are bound by other proteins that are necessary for their activity. Cyclophilin (peptidyl-prolyl isomerase A (PPIA)) is one such isomerase protein that is inhibited by ciclosporin (Gengaf, Neoral discovered 1969 Norway, 1972 immunosuppressive, approved 1983). FKBP1A (FKBP-12) is another peptidyl-prolyl cis-trans isomerase of the immunophilin family and is inhibited by FK506-tacrolimus (Prograf discovered 1984 Japan, immunosuppressive approved 1994 liver transplantation). Peptidyl prolyl isomerase inhibition by either pathway prevents calcineurin, a cytoplasmic phosphatase, from activating the nuclear factor of activated T cells cytoplasmic (nFATc), into the transcription factor NF-AT which normally increases expression of IL-2 and related cytokines.

Question 56

how does metformin work?

Answer 56

Metformin (C4H11N5) works by inhibition of complex I, activation of AMP-activated protein kinase (AMPK), inhibition of glucagon induced cAMP>PKA, inhibition of mito glycerophosphate dehydrogenase.
generates small heterodimer partner (SHP, NROB2 nuclear receptor subfamily 0,group B member2) which inhibits hepatic gluconeogenesis.
Metformin reduces protein synthesis and autophagy so that life extension occurs.
Complex one exists in active and de-active states. Metformin is more active in the de-active state.
AMP-activated protein kinase (AMPK) when stimulated by metformin reduces insulin resistance, preserve pancreatic beta cell function, increases HDL, decreases LDL density, decreases triglycerides, decreases renal microalbumin excretion, decreases blood pressure, decreases the VSMC proliferation/migration and arterial wall, decreases PAI-1 levels, decreases C-reactive protein, decreases TNF alpha, increases adiponectin, decreases free fatty acids. Stimulates EC nitric oxide release, ameliorate EC activation, attenuates the glucose-DAG-P KCb pathway, affects contractile, inflammatory thrombotic dimensions of endothelial dysfunction.