MOA: osmotic diuretic agent,  Increases urine flow by preventing the reabsorption of H2O in the ascending limb of the Loop of Henle

Pharm Effects: *urine flow rate can inc from 1ml/min to 10+ ml/min. *inc urinary excretion of Na, K, Mg, Ca, Cl, HCO3, PO4. *magnitude of solute/H2O loss is directly proportional to the amt of mannitol excreted in the urine

Therapeutic Uses: *Must be given IV. *prevent complete renal failure in pts w/ ARF. *dec intraocular pressure in glaucoma*dec intracranial pressure if intracranial bleeding is not involved*prevent renal toxicity of certain cmpds such as cisplatin. Ampho B, cyclosporine & myoglobin

Toxic Effects: overexpansion of intravascular volume leading to CHF & pulmonary edema; headache, nausea, & hyponatremia

ACETAZOLAMIDE

MOA:Carbonic Acid Inhibitor in the Proximal Tubule

PHARM EFFECTS: prevents reabsorption of HCO_3^-, Na & water. K⁺ secretion is increased, Cl^- excretion is decreased

THERAPEUTIC USES:glaucoma, altitude sickness, alkalinization of urine to increase acidic drug secretion (i.e. aspiring poisoning)

TOXICITY: Hyperchloremic metabolic acidosis due to loss of bicarbonate and impaired secretion on H⁺

FUROSEMIDE

ETHACRYNIC ACID

BUMETANIDE

MOA: "loop diuretic". Must enter tubule to exert action. Produces rapid diuresis (15 min) of short duration (2-3 h). Ihibits Na/K/2Cl cotransport in the Loop of Henle.

PHARM EFFECTS: Causes immediate increase in RBF & GFR. Immediate increase in renin secretion- leads to secondary hyperaldosteronism. Inc loss of K⁺ & H⁺ leads to metabolic alkalosis. Inc Ca, Mg excretion. Inc urate reabs. in proximal tubule. Inability of kidney to []/dilute urine.

THERAPEUITC USES: Acute pulmonary edema. Edema in cardia, hepatic & renal disease. Hypercalcemia

TOXICITY: Secondary Hyperaldosteronism, Hypokalemia (hypochloremic metabolic alkalosis: musc. weakness, mental confusion & cardiac dysrhythmias). Hypomagnesemia, Hyperuricemia (gout), Dilutional hyponatremia & hyperglycemia (only Furosemide). Tinnitus (esp. Ethacrynic acid). Azotemia & coma in severe renal/hepatic disease.

HYDROCHLOROTHIAZIDE

METOLAZONE

MOA: Inhibit active NaCl reabsorption in the distal tubule. Impair kidney to produce a dilute urinte (urine hypertonic). Enhance urate reabsorption in proximal tubule. Dec. excretion of Ca. Inc excretion of Mg & K & renin (secondary hyperaldosteronism)

PHARM EFFECTS: orally active (except Metolazone, also works in proximal tubule). not modified by acidosis/alkalosis. Diruresis is rapid & long duration (12h). must enter tubule to be active. GFR is consistently reduced. Ineffective if GFR < 25ml/min (except Metolazone)

THERAPEUTIC USES: 1st line tmt for Hypertension. Management of edema due to CHF, renal failure & hepatic cirrhosis. Management of Hypercalcinuria in pts w/ kidney stones. Diabetes insipidus (less Vl sent to CD)

TOXICITY: Secondary hyperaldosteronism. Hypokalemia (hypochloremic metabolic alkalosis). Hypomagnesemia (cardiac dysrhythmias). Hyperuricemia. Dilutional hyponatremia. Hyperglycemia (blocks insulin secretion). Azotemia & coma. 

TRIAMTERENE

AMILORIDE

MOA: K sparing diuretics. Inhibit Na reab. by blocking Na channels on luminal (apical) membranes of principal cells inthe distal tubule & collecting duct. Weak diuretics. 

PHARM EFFECTS: Inhibit secretion of H⁺ & K⁺ . Inc excretion of water, Na, Cl, & HCO_3^-

THERAPEUTIC USES:use w/ a loop diuretic (thiazide) to lessen the hypokalemeia. Tmt of Cystic Fibrosis (amiloride slows mucus accumulation.

TOXICITY:  Hyperkalemia (Do NOT give w/ K supplements)

MOA: K sparing diuretic. Blocks aldosterone receptors in the distal tubule (requires presence of Aldosterone).

PHARM EFFECTS: Weak diuretic. Inc excretion of water, Na, Cl, HCO3 & Dec. excretion of K. Very long duration of action (half life= 24 h)

THERAPEUTIC USES: Used w/ thiazide to enhance diuresis & lessen hypokalemia. Refractory edema. Primary hyperaldosteronism. Cirrhosis & nephrotic syndrome. Heart failure (dec. L. vent wall stiffness caused by aldosterone)

TOXICITY: Hyperkalemia (Do NOT use K supplements). It is a partial agonist at androgen, estrogen & progesterone receptors, thus in Males- gynecomastia & azoospermia. Females- menstrual irregularity & hirsutism 

BICALUTAMIDE

NILUTAMIDE

FLUTAMIDE

MOA: ANTIANDROGENIC. Loss of feedback inhibition to the hypothalamus, so plasma LH Inc. & thus testosterone syn is inc.

PHARM EFFECTS:

THERAPEUTIC USES: Prostatic Carcinoma (Bicalutamide is given w/ GnRH analog b/c testosterone limits its anti-androgenic effects)

TOXICITY: Bicalutamide is preferred over flutamide b/c it has less hepatic toxicity and can be taken once a day.

LEUPROLIDE

GOSERELIN

MOA: GnRH receptor agonist. Act at the pituitary gland to shut off the release of LH & FSH.

PHARM EFFECTS:  Intially stimulate release of FSH & LH (& plasma testosterone rises in males). But given in non-pulsatilie fhashion leads to Dec. secretion of LH and plasma testosterone is suppressed w/in 2 wks

THERAPEUTIC USES: Prostatic Carcinoma (Bicalutamide is given w/ GnRH analog b/c testosterone limits its anti-androgenic effects). Endometriosis & uterine fold tumors. Prococious puberty.

TOXICITY: Hot flushes & sweating; edema; gynecomastia; Dec. libido

DOXAZOSIN

TAMSULOSIN

MOA: Alpha₁ adrenoceptor antagonists (abundant in smooth muscle of the prostate, porstatic capsule, urethra & bladder neck). Tamsulosin is selective for alpha_1A (less dizziness & hypotension)

PHARM EFFECTS: reversible relaxation of this smooth muscle resulting in Dec urethral ressitance to flow (More rapid initiation of micturition, greater peak flow rate, more complete emptying of the urinary bladder; improves urgency, hesitancy, weak stream & nocturia). Doxazosin has half life of 22 h

THERAPEUTIC USES: Obstructive symptoms of BPH (benign prostate hyperplasia). Can treat hypertention & BPH in the same pt.

TOXICITY: Postural hypotension. Impotence. Dizziness, somnolence, asthenia/fatigue, nasal congestion, peripheral edema

FINASTERIDE

DUTASTERIDEα

MOA:  5α-reductase inhibitors. Prevents conversion of terstosterone to dihydrotestosterone (DHT). Finasteride selectively inhibits type 2 enzyme. 

PHARM EFFECTS:  DHT plasma [] falls by 70% & testosterone rises by 10%. Prostate decreases in size w/in 3 mths

THERAPEUTIC USES: BPH (decreased need for a TURP of TUNA- trnasurethral needle ablation). Male pattern baldness (1mg)

TOXICITY:  impotence. Finasteride (5mg p.o.) suppresses the plasma [] of prostate specific antigen (PSA) by 50% thus a new baseline PSA must be made one year after tmt.

MOA: Long acting synthetic analof of vasopressin (AVP) (6-20h). Selective for V2-receptor found in principal cells of the late distal tubule & collecting duct. Can be given by nasal spray before bedtime to enhance renal reab. of water and dec. urinary volume

PHARM EFFECTS:  Decreaseed nocturnal production of urine

THERAPEUITIC USES: Voding dysfunction (nocturnal enuresis)

TOXICITY:  Allergic rhinitis or nasal congestion from URI slow absorption

ALPROSTADIL:  PGE1-receptor agonist, erection in 5 min subsides in 60-90 min (used for pts who do not respond to Sildenafil)

PDEase5 Inhibitors: cGMP not degraded, thus dephosphorylation of the MLC prevents interaction of actin w/ smooth mus and thus smooth musc relaxes. Toxic Side effects: "Smurf" vision (impaired blue-green discrimination), NAION non-arteritic ischemic optic neuropathy, headache, & flushing. Drug-drug interactions w/ nitrates & alpha blockers

             SILDENAFIL: onset= 30-60 min; acts for 4-5 h

             VARDENAFIL: onset= 60 min; acts for 4-5 h

             TADALAFIL: onset=  30-45 min; acts for 24 h

PREDNISONE

PREDNISOLONE

MOA: PREDNISONE CONVERTED TO PREDNISOLONE BY HEPATIC 11β-HYDROXYTEROID DEHYDROGENASE.

       1. Leukocytopenia: Reduction in circulating T & B lymphocytes.

       2. Interfere w/ function of macrophages/monocytes by blocking expression of genes for IL-1 and IL-6.

       3. Interfere w/ helper T cells by blocking expression of genes for IL-2, IL-4, TNFβ and IFNγ

PHARM EFFECTS: Inhibition of cellular & humoral immunity (by inhibiting fxn of APCs, helper T cells, clonal expansion of T & B cells, cytotoxic T cells, expression of MHC II antigens & production of antibodies)

THERAPEURIC EFFECTS:Organ transplantation & autoimmune diseases

TOXICITY:infection prone

MOA:FAT SOLUBLE PEPTIDE ANTIBIOTIC. Prevents transcription of genes for IL-2, TNFβ and IFNγ. Decreased expression of IL-2 receptors on surface of helpter T cells. Binds to cyclophilin and forms a complex which inhibits the enzymatic activity of calcineurin (which would have dephosphorylated cytosolic NFATC to code for IL-2, TNFβ & IFNγ

PHARM EFFECTS: Primarily suppresses cellular immunity. Doesn't affect actions of suppressor T-cells, No myelosuppression

THERAPEUTIC USES:organ transplantation, Graft versus host disease, Autoimmune disease

TOXICITY: Nephrotoxicity. Metabolized by hepatic CYP450 thus drug interactions

MOA: Binds to cytosolic protein FKBP of helper T-cells:  complex which inhibits the enzymatic activity of calcineurin (which would have dephosphorylated cytosolic NFATC to code for IL-2, IL-2 receptors, TNFβ & IFNγ. 100X more potent than Cyclosporine

PHARM EFFECTS: Primarily suppresses cellular immunity. Doesn't affect actions of suppressor T-cells, No myelosuppression

THERAPEUTIC USES:good for prevention of acute rejection; allows withdrawal of tx w/ corticosteroids. Rescue therapy when OKT-3 fails.

TOXICITY: Nephrotoxicity. Metabolized by hepatic CYP450 thus drug interactions

MOA:Binds to the immunophilin FKBP-12. This complex inhibits a protein kinase mammalian target of rapamycin (mTOR), critical for progression from G1 to S-phase of the cell cycle.

PHARM EFFECTS: Blockade of mTOR prevents the activation & clonal expansion of T & B-cells. Also inhibits the syn of immunoglobulins by B cells

THERAPEUTIC USES:Combined w/ cyclosporine for acute rejection of renal allografts (synergistic)

TOXICITY: anemia (30%) thrombocytopenia (20%), hypertension & hyperlipidemia (45%)

MOA:A potent inhibitor of inosine monophosphate dehydrogenase, an enzyme critical in the de novo syn of purine Guanine by T & B lymphocytes (b/c these cells have no alternative pathway (HGPRT) pathway for purine biosynthesis)

PHARM EFFECTS: Cytotoxicity. Suppresses lymphocyte proliferation and antibody syn by B cells. Prevents leukocyte recruitment by inhibiting glycosylation of lymphocyte glycoproteins.

THERAPEUTIC USES:Renal, cardiac & hepatic organ transplantation. Used as substitute for azathioprine

TOXICITY: Sepsis (esp cytomegalovirus), Diarrhea, leukopenia & GI hemorrhage. 

MOA:Monoclonal antibody directed against the CD3 complex of helper T cells & cytotoxic T-cells. This blocks the binding of the foreigns antigen presented by APC and helpter T cell cannot be activiated to produce IL-2.

PHARM EFFECTS: T cell receptor antigen recognition site undergoes endocytosis, T cells become inactive and are removed from circulation by reticuloendothelial system. Prevents direct activation of helper T cells, B cells and plasma cells by f-MHC II carried by passenger leukocytes. Blocks functionof cytotoxic T cells.

THERAPEUTIC USES:Prophylaxis for early rejection & tmt of rejection crisis.

TOXICITY: Cytokine release syndrome (anaphylactic-like reaction). Pulmonary edema, nephrotoxic, neurologic complications, viral infections & neoplasms

MOA:A chimeric MAB against the α-chain (CD25) of the IL-2 receptor of the T-cell. 

PHARM EFFECTS: Prevents activation and proliferation of T cells

THERAPEUTIC USES:renal transplantation (1st dose w/in 2 h of start of surgery & 2nd dose 4 days after transplantation)