Renal pharm Flashcards
acute kidney injury- nephrotoxicity
occurs after exposure to drugs, medical procedures, and toxins.
High incidence of acute kidney injury in patients receiving antibiotics, chemotherapy, or radiocontrast dyes.
Also a complications of tharacic surgery
Chronic kidney disease develops in 20-30% of acute kidney survivors
Current treatment involves fluid and blood pressure maintenance and hemdialysis
Mechamism of acute kidney injury
- Arterial occlusion (transplant surgery), Hypotension (volume depletion), Shock (cardiogenic septic)
- Renal ischemia (reperfuision)
- Microvascular dysfunction, excess vasoconstriction, inflammation, oxidative stress, endothelial injury, endothelial-leukocyte interactions
- Mismatch between O2 consumption and O2 supply
- Renal tissue hypoxia
- Tubular necrosis and apoptosis
Emerging pharmacological agents moa for acute kidney injury
- Antiapoptotic (Caspase inhibitors, Minocycline)
- Anti inflammatory (Adenosine A2A agonist, Phosphatidylserine binding protein)
- Antisepsis (Insulin)
- Growth Factor (recombinant erythropoietin)
- Vasodilator (Fenoldopam-dopamine, ANP, Nitro oleic acid analogs)
Chronic kidney disease causes and treatments
Diabetic nephropathy, HTN, Glomerulonephritis, HIV nephropathy, Reflux nephropathy in children, Polycystic kidney disease, kidney infection and obstructions
Treatment for chronic kidney disease, inhibit RAAS
RAAS inhibitors decrease progression of albuminuria, GFR decline, risk of ESRD
Beneficial effects of inhibitors: only in part due to BP reduction, extend to CKD regardless of etiology, occur with both ACEis and ARBs, together better than alone
NSAIDs damage the kidney further, may interact with ACEs and ANG receptor antagonists
Treatment of diabetic nephropathy
Management of primary disorder paramount, Good glycemic control (HbA1C<7%), BP coontrol under140
Meds to minimize Proteinuria (Acei and ARBs
anemia in chronic kidney diseases
Erythropoietin- glycosylated protein hormone produced primarily in the kidney
REgulates RBC production by production by reducing apoptosis and stimulating differentiation and proliferation of erythroid progenitor cells. Deficient in End stage renal disease (ESRD)
Symptoms: Fatigue and decreased cognition, causes (Kidney releases ETP in response to hypoxia in endothelial cells of peritubular capillaries–> bone marrow–> RBCs)
Epoetin
IV or Sub Q
Human recombinant synthesized, response more rapid with IV but greater response with subQ, E poetin half lige (4-6 hours) administered 2-3 times/wk
SE: NVD, headache, influenza like symptoms, HTN ( dose dependent and can be severe leading to encephalopathy and seizures, thrombosis of arteriovenous shunts, Pure red cell aplasia subQ admin in renal failure could have Antibodies of Epoetin
Hypocalcemia in CKD
CKD–> low renal phosphorous clearance–> hyperphosphatemia and increased FGF23–> reduced Vit D–> hypocalcemia, 2’ hyyperPTH
excitability of nerves and muscles and regulates permeability of cell membranes, also integrity of cell membranes
Ca essential for excitation and coupling of all types of muscles, exciteation and secretion of endocrine and exocrine glands, and release of NT from nerve ending, Intracellular messenger for hormones, autacoids and transmitters, impulse generation and condution in heart, coagulation of blood, structural function of bone and teeth
Plasma calcium
regulated by 3 hormones, PTH calcitonin, and calcitriol (vit D) 9-11 mg/dl
40% bound to plama protein- 10% citratem carbonate and phosphate and 50% is free ionized and important form, Hypoalbuminemia (no drecrease in calcium concentration)
Acidosis- favors ionization, alkalosis disfavors ionization hyper ventilation precipitates tetany and laryngospasm in calcium deficiency
Causes secondary hyperpth ( due to decreased vit D3, dec serum calcium, increased phosphorous)
calcitriol and vit D analogs moa
enhancement of absorption of Calcium and Po4 from intestine, by increasing the synthesis of calcium channels and a carrier calcium binding protein CaBP or calbindin
Binds to cytoplasmic vit D receptor (VDR)- translocation increased synthesis of mRna- regulation of protein synthesis
Calcitriol also enhances recruitment and differentiation of osteoclast precursor for remodeling- resorption of calcium and PO4 from bone, also enhances renal tubular REAB of calcium
SE of Calcitriol
increases intestinal absorption of Ca and phosphate and increases Ca and phosphate mobilization from bone, calcitriol can result in Hyper Ca and PO4
Second and 3rd generation of Vit D analogs have more affinity to the kidney and a lower incidence of Hyper Ca and PO4, and better PTH control
Ergocalciferol is inactive (needs hydroxylation in kidney)
Kidney disease- the hydroxylated active forms (alfacalcidol or calcitriol need to be used)
Alafacalcidol and calcitriol have really short half lives, paricalcitol requires IV injection, unwanted effect (excessive dosing leads to hypercalcemia
Signs and treatment of vit D- fractures and hyper PTH
Phosphate binders
Calcium carbonate, calcium acetate, lanthanum carbonate
GI - phosphate absorption by reacting with phosphate and form insoluble compound
Sevelamer- calcium and aluminum free polymeric structure (GI se/hypercalcemia)
bisphosphonates- hypercalcemia
RONATES
Bisphosphonates are pyrophosphate analogs that bind to hydroxyapatite in bone to inhibit bone resorption
Zoledondrates can suppress bone rresorption for up to a year after a single dose, removed by kidney, unwanted SE (GIT osteonecrosis of jaw)
Calcitonin
Produced by parafollicular or C cells of the thyroid gland, secreted when plasma calcium level rises, main action is the lowering of plasma calcium by limiting bone resorption and it increases phosphate excretion in the urine, intramuscular or subQ injection- half life 20 minutes
SE: facial flushing in most patients, neural (headaches, dizziness), GI (nausea, vomiting abdominal pain, diarrhea), taste disturbance
hyperuricemia and gout in kidney disease
Kidney eliminates urate from plasma, 8-12% of Urate filtered load is excreted
Colchicine (reduces inflammation, given every 6-12 hrs, ) Unwanted side effects (GIT and rash)
Hyperuricemia and gout in kidney disease,
Xanthane Oxidase inhibitor - oral
Allorpurinol- purine
Febuxostat: Non- purine, competitve enzyme inhibitors, variable half life 1-15 hours (renal excretion), SE: GI upset, acute gout (release of Urate from tissue deposits, HS to allopurinol rashes especially in renal disease pts), Drug interaction inhibit metabolism of azathioprine
Rasbuircase iv admin, recombinant version of enzyme urate oxidase, metabolized by peptide hydrolysis in plamsa, used 1’ as prophylaxis during chemo (CKD), SE: fever NVD, HS hemolysis
Renal replacement therapy and transplantation
you want a living donor,, malignant skin tumors, CVD, need immunosuppression to combat kidney transplant rejection
Renal transplant, calcineurin inhibitors
Origin: Cyclosporine (small cyclic polypeptide, fungal origin), Tacroolimus (macrolide isolated from streptomyces)
MOA: bind to cytosolic receptor proteins, cyclophillin (cyclosporine), FKBP12 (tacrolimus)
Complex binds to and inhibits action of calcineurin, inhibits the transcription of cytokines, such as IL2 that aare essential for T cell activation and proliferation
Cyclosporine (oral or IV): concentrates in tissue- liver kidney, spleen, bone marrow, MEtabolized extensively by CYP3A4 in liver, long half life (27 hrs)
Cyclosporine SE
Nephrotoxic, HTN and fluid retention, hepatic dysfunction, tremor, headache, fatigue, NVD, Hypertrichosis, gum hypertrophy, Hyper Lipidemia, Hypo magnesium, kalemia
tacrolimus
calcineurin inhibitor
oral IV, more water soluble metabolized by liver, highly variable half life, monitor trough blood concentration essential, doesnt stimulate TGF B, unwanted side effects (pleural and pericardial effusions, cardiomyopathy in children)
calcineurin inhibitor side effects
Hepatotoxicity: liver function should be monitored at regular intervals
Cardiovasular (HTN HLIP): fewer tacrolimus- treated patients require antihypertensive meds, Tacrolimus impact on lipid levels is less than that seen with cyclosporine
Glucose intolerance: recent studies indicate little differences tacrolimus and cyclosporine
Neurotoxicity (Tremor headache, insomnia, paresthesia)- seem more with tacrolimus
calcineurin
Nephrotoxic agents (NSAIDs, vancomycin, Ganciclovir, aminoglycosides)- monitor renal function, NSAIDs may have increased nephrotoxicity with hepatic impairment
Potassium-sparing diuretics (hyperkalemia has been reported)
Antacids (magnesium and aluminum antacids may inhibit absorption of CNIs) if necessary should be taken 2hrs after CNI dose
HMG CoA reductase inhibitors (increased risk of rhabdomyolysis, BM suppression)
mTOR sirolimus
Macrolide, Sirolimus binds to FKBP12, complex binds and modulates the activity of mTOR, blocks signal 3 (inhibition of cytokine/ IL2 induced cell cycle progression from G1 to S phase)
Oral Gut absorption odulated P gp, metabolized by intestinal and liver CYP450, very long half life (60 hrs)
Antiproliferative Agents- mycophenolate Mofetil
Mycophenolic acid (MPA): isolated from penicillim Mycophenolate mofetil MMF: a prodrug of MPA
MOA: Competitive reversible, inhibition of IMPDH a critical rate limiting enzyme in de novoe purine synthesis
Lymphocytes dependent on de novo pathway vs salvage pathway utilized by other cell types, Inhibits proliferation of B and T cells
