RENAL_PHARM_MS2

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soren101
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105119
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RENAL_PHARM_MS2
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2011-10-03 12:16:44
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DIURETIC IMMUNOSUPPRESSIVE ANDROGEN PHARMACOLOGY MS2
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DIURETIC IMMUNOSUPPRESSIVE ANDROGEN PHARMACOLOGY MS2
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  1. MANNITOL PHARMACOLOGICAL EFFECTS
    Osmotic diuretic agent:

    Decr Na reabs in thick asc limb

    Freely filtered at glomerulus.

    • Not reabs & metabolically inert.
    • -----------------------------------------------
    • PHARM

    Surrounded by layer of tightly bound H2O molecs → H2O lost in urine when mannitol excr

    • Incr RBF & GFR but major diuretic effect:
    • --Prevent reabs of H2O in THIN desc limb → incr urine flow

    H2O retention by mannitol→ decr NaCL conc of urine entering asc limb →

    Decr Na gradient which normally drives NaCl reabs in asc limb →

    Less NaCl reabs in asc limb

    ***

    Expansion of intravascular vol by mannitol →

    Incr renal medullary blood flow →

    Washing out NaCl & urea →

    Reduces interstitial osmotic gradient

    H2O loss enhanced b/c interstitial osmotic gradient is the factor which drives H2O reabs in presence of ADH

    ***

    • NET EFFECT:
    • · Urine flow rate can incr from 1ml/min to 10+ ml/min

    · Incr excr of Na, K, Mg, Ca, Cl, HCO3 & PO4

    · Magnitude of solute/H2O loss -- directly proportional to amount of mannitol excr
  2. MANNITOL THERAPEUTIC USES AND TOXICITY
    Osmotic diuretic agent:

    Decr Na reabs in thick asc limb

    1. Must be given i.v. (use limited to inpatients). Need also give i.v. fluids to replace H2O loss!!!!

    2. Prevent complete renal failure in pts w/ ARF

    3. Decr intraocular pressure in glaucoma

    4. Decr intracranial pressure if intracranial bleeding is not involved (b/c blood vol incr w/ Rx)

    • 5. Prevent renal Toxicity/Side Effects of certain cmpds such as cisplatin. Ampho B, cyclosporine & myoglobin
    • -----------------------------------
    • TOX

    1. Overexpansion of intravascular vol → leading to CHF & pulmonary edema

    2. Headache

    3. Nausea

    4. Hyponatremia
  3. ACETAZOLAMIDE MOA AND PHARMACOLOGICAL EFFECTS
    Carbonic anhydrase (CA) inhibitor:

    Decr epith transport of Na in proximal tubule

    Blockade of CA →

    Prevents reabs of filtered HCO3 →

    Prevents reabs of Na & H2O →

    Urinary pH incr (from 6 → 8.2)

    Loop of Henle is impermb to HCO3 → cannot completely compensate for loss of Na reabs in PT → urine at distal tubule still high in Na & HCO3

    ***

    • 1. Marked incr in K secretion
    • --Asc limb captures ~ all of excess Cl & part of Na coming from PT
    • --Incr’d Na reaching EDT w/ (non-permb) HCO3 instead of (permb anion) Cl → less Na reabs
    • --Na conserved only by cation exchange w/ K in LDT/CD

    2. Incr urine vol & incr excr of Na, K & HCO3

    • 3. Decr Cl excr
    • ---------------------------------------
    • PHARM

    CA greatly incr rate of reabs of HCO3 in PT (80%) & EDT (20%)

    Acetazolamide: Inhb 85-90% of CA in PT → only 35% of total HCO3 reabs inhb (~ other pathways)

    Acetazolamide: Relatively weak diuretic agent → Both filtered & secreted into tubule via organic acid transport system
  4. ACETAZOLAMIDE THERAPEUTIC USES AND TOXICITY
    Carbonic anhydrase (CA) inhibitor: Decr epith transport of Na in proximal tubule

    • 1.
    • Glaucoma

    • 2.
    • AltitudeVsickness: Works best when given prophylactically

    • 3.
    • AlkalinizationVof urine → incr loss of acidic drug in drug intoxication (e.g. aspirin poisoning)
    • ---------------------------------
    • TOX

    *Hyperchloremic metabolic acidosis due to HCO3 loss & impairment of H secretion

    When HCO3 is lost → body retains Cl & vice versa
  5. FUROSEMIDE MOA AND PHARMACOLOGICAL EFFECTS
    LOOP DIURETIC

    *Inhb active Na/K/2 Cl cotransport in medullary & cortical segments of Loop →

    Decr NaCl reabs

    *Large doses fursosemide: May inhb CA → affect Na reabs in PT

    *Stim renal synth of vasodilatory PGs → immed incr RBF & GFR

    • **Inhb Na/K/2 Cl symporter in macula densa →
    • --Block tubuloglomerular feedback → Immed incr GFR
    • --Immed incr renin secrtn → incr [Ang II]P → chronic, 2* hyperAldo

    • *Incr Na delivery to DT, incr DT flow & hyperAldo → Incr K secrtn & urinary loss → metabolic alkalosis (corrected w/ KCl)
    • --------------------------------------
    • PHARM

    Vigorous natriuresis (25-30% of filtered load) occurs since the DT can’t compensate by greatly incr Na reabs

    Filtered & secreted into PT via organic acid transport system. Must enter tubule to exert action.

    Actvy NOT affected by acidosis or alkalosis.

    1. Incr RBF & GFR (partially PG-dependent)

    • 2. Incr K secretion due to:
    • --Incr Na delivery to DT
    • --Incr DT flow
    • --2* hyperAldo → incr K loss → metab alk (correceted by KCl)

    3. Incr Ca & Mg excr

    4. Incr urate reabs in PT (→ gout)

    5. Decr reabs of NaCl in Loop → Lose ability to conc/dilute urine

    6. Incr urine vol & incr excr of Na, K, Mg, Ca, Cl, HCO3 & PO4
  6. FUROSEMIDE THERAPEUTIC USES AND TOXICITY
    LOOP DIURETICS

    *Inhb active Na/K/2 Cl cotransport in medullary & cortical segments of Loop

    Given p.o. or i.v. (parenterally)

    Rapid diuresis (15 min) of short duration (2-3 h)

    ***Effective if GFR < 25 ml/min

    • 1.
    • Acute pulmonary edema***
    • ***DOC: drug: i.v. furosemide

    • 2.
    • Management of edema
    • in cardiac, hepatic & renal disease
    • --Since incr’d RBF & GFR → drugs useful to Rx chronic renal failure & nephrotic syndrome

    • 3.
    • Hypercalcemia (solid tumors)

    **EXAM: Rx hyperCa++ w/ Ringer’s lactate soln/i.v. fluid AND furosemide

    • Need admin i.v. fluids at same rate urine output to
    • compensate for H2O loss
    • -------------------------------------
    • TOX

    • 1.
    • 2o hyperAldo: from incr’d
    • renin secrtn & subsq incr [Ang II]P

    • 2.
    • Hypokalemia → musc weakness, mental confusion & cardiac dysrhythmias
    • --Excess loss of NaCl & KCl →HypoCl metabolic alkalosis. 2o hyperAldo → hypoK

    • 3.
    • Hypomagnesemia→ poss cardiac dysrhythmias

    • 4.
    • Hyperuricemia → can ppt attack of gouty
    • arthritis

    • 5.
    • Dilutional hyponatremia: can’t excrete excess H2O intake

    • 6.
    • Hyperglycemia
    • (furosemide only)



    • 7.
    • Azotemia & coma in severe renal & hepatic disease. HypoK → stim renal NH3 production



    • 8.
    • Orthostatic hypotension:
    • from depletion of plasma vol

    • 9.
    • ***tinnitus & poss reversible hearing loss (CN VIII!) w/ large doses, esp ethacrynic acid
  7. BUMETANIDE
    SAME AS FUROSEMIDE

    LOOP DIURETICS

    *Inhb active Na/K/2 Cl cotransport in medullary & cortical segments of Loop →

    Decr NaCl reabs .
  8. ETHACRYNIC ACID
    SAME AS FUROSEMIDE

    LOOP DIURETICS

    *Inhb active Na/K/2 Cl cotransport in medullary & cortical segments of Loop →

    Decr NaCl reabs .

    BUMETANIDE & FUROSEMIDE
  9. HYDROCHLOROTHIAZIDE MOA & PHARMACOLOGICAL EFFECTS
    THIAZIDES

    Inhb active NaCl reabs in DT

    Large doses of some thiazides can inhb CA & affect Na reabs in PT.

    Urinary pH incr (from 6 to 7.4)

    Rare b/c dose ~small to prevent hypokalemia

    Impair ability to produce dilute urine → urine always hypertonic.

    Excessive H2O intake poss → dilutional hypoNa.

    • All drugs given p.o. & ≈ efficacious, except Metolazone also inhb Na reabs in PT by mech NOT involving CA.
    • ----------------------------------------
    • PHARM

    Secreted into PT via organic acid transport system. Must enter tubule to exert action.

    Actvy NOT affected by acidosis or alkalosis.

    Thiazides efficacy < loop diuretics b/c only 5-6% of filtered Na load excr

    Decr GFR (tho variable effects on RBF)

    ***

    1. Incr urate reabs in PT

    • 2. Decr Ca excr → plasma Ca only slightly incr
    • if Ca metab is normal

    3. Incr Mg excr

    • 4. Progressive contraction of ECF vol → actvn
    • of sympathetic nerv systm & incr renin secretion → incr Ang II → 2o hyperAldo

    • 5. Incr Na delivery to DT & 2o
    • hyperAldo → incr K excr

    • 6.
    • Incr excretion of H2O, Na, Cl, K & Mg. HCO3 excr incr w/ Lg doses
  10. HYDROCLOROTHIAZIDE THERAPEUTIC USES AND TOXICITY
    • THIAZIDE
    • --INH ACTIVE NaCl REABS IN DT

    Given p.o.

    Diuresis is rapid onset & of long duration (12 h)

    **HCTZ ineffective if GFR < 25 ml/min

    **metolazone still effective if GFR < 25 ml/min

    • 1.
    • hypertension***
    • ***DOC: thiazides (HCTZ)

    • 2.
    • Manage edema due to CHF, renal failure, cirrhosis, premenstrual weight gain & hormone
    • therapy w/ estrogen

    • 3.
    • Manage hypercalcinuria
    • in pts w/ renal calculi composed of Ca salts

    • 4.
    • diabetes insipidus:

    Natriuresis → decr plasma vol → incr incr efficiency of solute/H2O reabs in PT → less vol to CD.

    • Also, inhb of NaCl reabs in EDT → further impairs renal dilution.
    • ------------------------------------------
    • TOX

    • 1.
    • 2o hyperAldo: from incr’d
    • renin secrtn & subsq incr [Ang II]p

    • 2.
    • Hypokalemia → musc weakness, mental confusion & cardiac dysrhythmias

    Excess loss of NaCl & KCl →HypoCl metabolic alkalosis. 2o hyperAldo → hypoK

    • 3.
    • Hypomagnesemia → poss cardiac
    • dysrhythmias

    • 4.
    • Hyperuricemia → can ppt attack of gouty arthritis

    • 5.
    • Dilutional hyponatremia: can’t
    • excrete excess H2O intake

    • 6.
    • Hyperglycemia & aggravation of DM: due to blockade of insulin secretion

    • 7.
    • Azotemia & coma in severe renal & hepatic disease. HypoK → stim renal NH3 production
  11. METOLAZONE
    ANTIDIURETIC

    SIMILAR TO THIAZIDES
  12. AMILORIDE
    • Also Potassium
    • (K+)-sparing:

    Block Na channels on the luminal membrane of the principal cells in the DT & CD

    • Natriuresis NOT dependent on presence of endogenous Aldo
    • ------------------------------------
    • PHARM


    Weak diuretics: only 2-3% of filtered load is excreted

    • 1.
    • Inhb secretion of H ions
    • (Does NOT involve CA inhb)

    • 2.
    • Incr excretion
    • of H2O, Na, Cl & HCO3

    • 3.
    • Decr excretion of K & H
    • ----------------------------------------
    • THERA

    • Preferred over spironolactone b/c no S/E on sex
    • hormones.

    • 1.
    • Combo w/ Loop
    • Diuretics or thiazides: to enhance Na loss & lessen
    • HYPOkalemia caused by thiazide
    • e.g. HCTZ + amiloride

    • Cystic fibrosis: Inhalation of amiloride slows mucous accum & incr mucus clearance from lungs
    • -------------------------------------
    • TOX

    • *HYPERkalemia:
    • DO NOT use:
    • · w/ oral K supplements
    • · pts w/ severe renal insufficiency
  13. TRIAMTERENE
    DIURETIC

    SAME AS AMILORIDE

    • Also Potassium
    • (K+)-sparing:

    Block Na channels on the luminal membrane of the principal cells in the DT & CD

    • Natriuresis NOT dependent on presence of endogenous Aldo
    • ------------------------------------
    • PHARM


    Weak diuretics: only 2-3% of filtered load is excreted

    • 1.
    • Inhb secretion of H ions
    • (Does NOT involve CA inhb)

    • 2.
    • Incr excretion
    • of H2O, Na, Cl & HCO3

    • 3.
    • Decr excretion of K & H
    • ----------------------------------------
    • THERA

    • Preferred over spironolactone b/c no S/E on sex
    • hormones.

    • 1.
    • Combo w/ Loop
    • Diuretics or thiazides: to enhance Na loss & lessen
    • HYPOkalemia caused by thiazide
    • e.g. HCTZ + amiloride

    • Cystic fibrosis: Inhalation of amiloride slows mucous accum & incr mucus clearance from lungs
    • -------------------------------------
    • TOX

    • *HYPERkalemia:
    • DO NOT use:
    • · w/ oral K supplements
    • · pts w/ severe renal insufficiency
  14. SPIRONOLACTONE
    • Potassium (K+)-sparing: Blocks Aldo receptors
    • in DT

    ALSO ANDROGEN REC ANTAGONIST

    (seldom used as single drug)

    • 1.
    • Competitive steroid antagonist of aldosterone
    • receptors.

    • 2.
    • Also partial agonist (blocks full agonist func!!!) at androgen, estrogen & progesterone receptors

    • 3.
    • Also partially inhb CYP17, which synth
    • testosterone
    • -----------------------------------
    • PHARM

    Diuretic actv req presence of Aldo

    A weak diuretic: only 2-3% of filtered Na excr

    1. Incr excretion of H2O, Na, Cl & HCO3

    • 2. Decr K excr
    • --------------------------------------------
    • THERA

    Very long duration (t1/2 = 24 h)

    • 1.
    • Combo w/ thiazides: to enhance diuresis & lessen HYPOkalemia caused by thiazide

    • 2.
    • Refractory edema (nothing else
    • works)

    3. 1* HyperAldo

    • 4.
    • Cirrhosis & nephrotic syndrome: (edema not in interstitium) Intravascular hypovolemia → 2o
    • hyperAldo → incr K loss

    • 5.
    • Heart failure: decr left
    • ventricular wall stiffness

    Rx hirsuitism in females

    • ***COMBO:
    • --Androgen receptor antagonist & GnRH
    • receptor analog (to negate S/E of other drug)

    • --Use bicalutamide & a GnRH analog to to Rx prostate carcinoma
    • ------------------------------
    • TOX

    • *HYPERkalemia:
    • DO NOT use:
    • · w/ oral K supplements
    • · pts w/ severe renal insufficiency

    • *Partial agonist at estrogen, androgen &
    • progesterone receptors.

    • Also partially inhb testosterone
    • synth (weakly inhb CYP17)

    • : gynecomastia, azospermia
    • : menstrual irreg, hirsutism

    COMBO w/ biculatamide to negate S/E
  15. PREDNISONE & PREDNISOLONE
    IMMUNOSUPPRESSIVE

    CORTICOSTEROIDS

    Prednisone → converted to prednisolone by hepatic 11β-hydroxysteroid dehydrogenase

    • 1. Leukocytopenia
    • · Marked decr in circulating T & B cells
    • · Cells redistrb to spleen & bone marrow
    • · (bigger decr) T cell content << B cell content
    • · (bigger decr) CD4 cells << CD8 cells
    • · Decr circulating monocytes
    • · Decr circulating eosinophils & basophils
    • · *INCR circ neuts (due to release of mature cells fr bone marrow & decr movement fr blood into vascular tissue)

    2. Decr size & lymphoid content of lymph nodes & spleen

    3. **Inhb func of macrophages/monocytes (APCs) by blocking expression of genes for IL-1 & IL-6

    4. Interfere w/ func of helper T cells

    • 5. Interfere of lymphokine synth
    • · Inhibit expression of MHC II antigens by the allograft cells

    · Inhb actvn of helper T cells (blocks gene expression of IL-2 & IL-4, TNFβ & IFNγ)

    • Inhibit clonal expansion of T & B cells
    • -----------------------------------------------------
    • PHARM

    *generalized suppression of BOTH humoral & cell-mediated immunity

    *Corticosteroids DO NOT cause bone marrow depression

    NET EFFECTS:

    1. No actvn of helper T cells

    2. No actvn of CTL

    3. Prevent prolifn of T & B cells

    4. Suppress prodn of Ab by B cells

    5. Prevent synth of TNF & IFγ by helper T cells

    • 6. Reverses incr’d expressn of MHC II proteins
    • & adhesion molecules by allograft cells
    • --------------------------------------------

    • THERA
    • . Organ transplantation
    • - Kidney
    • - Heart
    • - Liver
    • - Bone marrow

    large dose: induction of immunosuppression & organ rejection crisis.

    Dose can be incr w/o bone marrow toxicity.

    smaller: maintenance immunosuppression

    • 2. Autoimmune diseases
    • --------------------------------------

    ADVERSE


    PREDNISONE mneumonic

    P = Peptic ulcers

    R = Retention of Na/H2O

    E = Extra deposits of fat on face and trunk (moon faces)

    D = Diabetes and chance in CHO metabolism

    N = Neurosis & psychosis

    I = Infection and poor wound healing

    S = Suppression of pituitary-adrenal axis

    O = Osteoperosis

    N = Negative N2 balance and muscle wasting

    E = Eye (cataracts and glaucoma)
  16. CYCLOSPORINE
    "ANCHOR OF IMMUNOSUPPRESSIVE THERAPY

    • MOA
    • Fat-solb peptide antibiotic
    • ·
    • Blocks helper T-cell activation!!!
    • ·
    • Prevents clonal expansion of T & B cells
    • ·
    • Prevents
    • activn of CTL
    • ·
    • Prevents
    • tsc of genes for IL-2, TNFβ & IFNγ
    • by binding to a cytoplasmic protein (cyclophilin)
    • ·
    • Prevents
    • tsc of genes for IL-2 receptors:
    • Decr expressn of IL-2 receptors on surface of helper T cells

    • ***
    • T cell receptor
    • actvn by APCs → incr IP3

    → incr free intracellular Ca++ conc

    • → actv calmodulin-dependent Ser/Thr phosphatase
    • (calcineurin), which dephosphorylates cytosolic NFATC (nuclear factor activated T cells)

    → dePi NFATC migrates to nucleus

    • → actv genes
    • for IL-2, IL-2 receptors, TNFβ & IFNγ

    **Cyclosporine binds to cyclophilin (cytoplasmic protein) → complex inhb enz activity of calcineurin.

    • Prevents dephosphorylation of NFATC → it can’t actv gene expression of IL-2, IL-2 receptors, TNFβ & IFNγ
    • -----------------------------------------------------

    • PHARM
    • ·
    • 1o suppresses CELLULAR immunity
    • ·
    • Suppresses Ab- mediated responses which involve helper T cells (but has little effect on Ab resp in which Ag stim B cells directly
    • ·
    • Does
    • NOT affect activity of suppressor T
    • cells
    • ·
    • NO
    • myelosuppression

    t1/2 = 10 – 15 h

    • Metabolized by CYP450
    • ------------------------------------------------

    THERA

    Given chronic p.o.

    • 1.
    • Organ
    • transplantation

    • Used w/ other immunosuppressv drugs in alllograft transpl of:
    • -
    • renal
    • -
    • cardiac
    • -
    • pancreatic
    • -
    • hepatic

    • 2.
    • **GVHD: After bone marrow transplant, donor T cells attack recipient → damage to skin & intestines

    • 3.
    • Autoimmune
    • disease
    • -
    • Rheumatoid
    • arthritis
    • -
    • Myasthenia
    • gravis
    • -
    • Psoriasis
    • -
    • Type I DM

    • Incidence of corticosteroid-resistant, acute organ rejection are LESS freq w/ tacrolimus than w/ cyclosporine
    • -------------------------------------------------

    ADVERSE

    • 1.
    • Nephrotoxicity→ HTN

    Damage PT cells in 75% pts.

    Enhanced nephrotoxicity w/ Ampho, AGs, NSAIDs

    2. Hepatotoxicity

    3. Incr viral infxns

    4. Gingival hyperplasia

    5. Neurotoxicity

    6. n/v, cramping, diarrhea, anorexia

    7. Hirsutism

    8. Drug interactions:

    • DECR cyclosporine
    • conc (incr CYP450):
    • ·
    • Rifampin
    • ·
    • Phenobarbital
    • ·
    • Phenytoin
    • ·
    • Carbamezepine

    • INCR cyclosporine
    • conc (inhb of CYP450):
    • ·
    • Ketoconazole
    • ·
    • Erythromycin
    • ·
    • Cimetidine

    Enhanced nephrotoxicity w/ Ampho, AGs, NSAID’s
  17. TACROLIMUS
    aka FK-506

    IMMUNOSUPPRESSIVE

    • A macrolide
    • antibiotic agent

    Binds to (cytosolic protein) FKBP of helper T cells

    • → tacrolimus-FKBP
    • complex inhb calcineurin

    • → Prevents
    • production of TNFβ & IFNγ , and
    • IL-2 & IL-2 receptors
    • -----------------------------------

    PHARM

    (same as cyclosporine)

    • 100X more potent >> than cyclosporine
    • ·
    • 1o
    • suppresses CELLULAR immunity
    • ·
    • Suppresses
    • Ab- mediated responses which involve helper
    • T cells (but has little effect on Ab resp in which Ag stim B cells directly)
    • ·
    • Does
    • NOT affect activity of suppressor T
    • cells
    • ·
    • NO
    • myelosuppression
    • -------------------------------------

    • THERA
    • 1.
    • Good for prevention of acute rejection
    • 2.
    • Allows withdrawal of Rx w/ corticosteroids

    • 3.
    • Incidence of corticosteroid-resistant, acute organ
    • rejection are LESS freq w/ tacrolimus
    • than w/ cyclosporine
    • 4.
    • Effective in rescue therapy when OKT-3
    • ineffective
    • ---------------------------------------------

    ADVERSE

    (same as cyclosporine)

    • 1.
    • Nephrotoxicity→ HTN

    Damage PT cells in 75% pts.

    • Enhanced nephrotoxicity w/ Ampho,
    • AGs, NSAIDs

    2. Hepatotoxicity

    • 3.
    • Incr
    • viral infxns
    • 4.
    • Gingival
    • hyperplasia

    5. Neurotoxicity

    • 6.
    • n/v,
    • cramping, diarrhea, anorexia

    • 7.
    • Hirsutism

    • 8.
    • Drug
    • interactions:

    • DECR cyclosporineconc
    • (incr CYP450):
    • ·
    • Rifampin
    • ·
    • Phenobarbital
    • ·
    • Phenytoin
    • ·
    • Carbamezepine

    • INCR cyclosporine
    • conc (inhb of CYP450):
    • ·
    • Ketoconazole
    • ·
    • Erythromycin
    • ·
    • Cimetidine

    • Enhanced nephrotoxicity
    • w/ Ampho, AGs, NSAID’s
  18. SIROLIMUS
    aka RAPAMYCIN

    • IMMUNOSUPPRESSIVE
    • ----------------
    • MOA

    DIFF FROM CYCLOSPORIN & TACROLIMUS

    BINDS TO IMMUNOPHILIN FKBP-12 BUT DOES NOT INH CALCINEURIN

    INH A PROT KINASE MAMMALIAN TARGET OF RAPAMYCIN mTOR WHICH IS CRITICAL ENZYME FOE SUCCESSFUL PROG FROM THE G1 TO S PHASE

    • DOES NOT INH IL-2 PROD BY ACTIVATED T CELLS
    • ----------------------------------

    PHARM

    BLOCK OF mTOR PREVENTS ACTIVATION AND CLONAL EXP OF T & B CELLS

    • ALSO INH SYNTH OF IMMUNOGLOBS BY B CELLS
    • -----------------------------------

    THERA

    USED w CYCLOSPORINE AND CORTs AS PROPHYLAXIS FOR ACUTE REJECTION OF RENAL ALLOGRAFTS

    NOT NEPHROTOXIC

    • SYNERGISTIC w CYCLOSPORINE SO DOSE OF CYCLO CAN BE DEC
    • ----------------------------

    TOX

    • ANEMIA
    • THROMBOCYTOPENIA
    • HYPERTENSION
    • HYPERLIPIDEMIA
  19. MYCOPHENOLATE MOFETIL
    IMMUNOSUPPRESSIVE

    ACTIVE METABOLITE = MYCOPHENOLIC ACID

    • Potent inhibitor of inosine monophosphate dehydrogenase (enz necess for de novo synth of
    • purine GUANINE by T & B cells)

    Acts specifically on lymphocytes b/c other cells have alternative pathway.

    • Unlike other cells derived fr bone marrow, lymphocytes have NO alternative pathway for purine biosynth.
    • --------------------------------

    PHARM

    • Cytotoxic
    • 1.
    • Suppresses
    • lymphocyte prolifn
    • 2.
    • Suppresses
    • Ab synth by B cells

    • Inhb glycosylation of lymphocyte glycoproteins
    • involved in cell adhesion → Prevents leukocyte recruitment
    • -------------------------------------------

    • THERA
    • 1.
    • Organ
    • transplantation
    • -
    • renal
    • -
    • cardiac
    • -
    • hepatic

    • 2.
    • Given p.o.
    • to prevent acute & chronic rejection of RENAL allografts, esp in pts who can’t tolerate cyclosporine or tacrolimus

    • 3.
    • Often used as a substitute for azathioprine
    • -----------------------------------------------

    ADVERSE

    • Cytotoxic
    • 1.
    • Sepsis,
    • esp CMV
    • 2.
    • Diarrhea
    • 3.
    • Leukopenia
    • 4.
    • GI hemorrhage
  20. OKT-3
    aka
    MUROMONAB-CD3
    IMMUNOSUPPRESSIVE CYTOTOXIC

    Monoclonal Ab directed at CD3 complex on CTL & helper T cells

    CD3 next to Ag recogn complex of helper T cell receptor

    **Binding of OKT-3 to CD3 → blocks binding of foreign Ag presented by APC

    → helper T cannot be actv’d to produce IL-2, etc.

    --Deactvn of CD3 → endocytosis of T cell receptor-Ag recogn site → func of CTL blocked

    • --Inactv T cells removed fr circ by reticuloendothelial system
    • ---------------------------------------------

    PHARM

    • ·
    • T cells disappear from circulation w/in minutes!!!!
    • ·
    • Prevents
    • actvn of helper T cells by APCs
    • ·
    • Prevents
    • direct actvn of B cells, T cells & plasma cells by f-MHC II
    • carried by passenger leukocytes

    • Blocks func of CTL
    • --------------------------------

    THERA

    • 1.
    • **DOC: prophylaxis
    • of early rejection

    • 2.
    • 1*
    • Rx for organ rejection

    • 3.
    • Rx of rejection crisis esp when corticosteroid-resistant rejection

    • 4.
    • Depletion of T cells from donor bone marrow
    • prior to transplantation → prevent GVHD
    • ----------------------------------------------

    TOX

    • 1.
    • Cytokine Release Syndrome (anaphylactic-like rxn)
    • ·
    • Symptoms
    • vary from fever, chills to life-threatening hypotension
    • ·
    • ~occurs
    • immed after 1st dose
    • ·
    • Can be
    • limited by pre-Rx w/ glucocorticoid

    • 2.
    • Pulmonary
    • edema

    • 3.
    • Nephrotoxicity

    • 4.
    • Neurological complications
    • --Vary fr mild headaches (35-50%) to aseptic meningitis (5-10%) or encephalopathy (2-5%) or hallucinations

    • 5.
    • Viral
    • infections

    • 6.
    • Neoplasms
  21. BASILIXIMAB
    IMMUNOSUPPRESSIVE

    MOA

    CHIMERIC MAB AGAINST a-CHAIN CD25 OF IL-2 RECEPTOR OF T-CELL

    • BINDING OF BASILIXIMAB TO T-CELL RECEPTORS PREVENTS ACT AND PROL OF T-CELLS
    • -----------------------------------------

    THERA

    • RENAL TRANSPLANTS
    • --1st DOSE GIVEN 2 hrs BEFORE START OF SURG
    • --2ND GIVEN 4 DAYS AFTER
  22. BICALUTAMIDE
    ANDROGEN RECEPTOR ANTAGONIST

    • Competitively
    • block androgen receptors

    Block androgen receptors in hypothalamus →

    Lose feedback inhb of LH secretion →

    Incr plasma levels of LH →

    Incr plasma levels of testosterone

    Rise in testosterone limits effect of anti-androgenic drug →

    • Use bicalutamide & a GnRH analog to Rx prostate
    • carcinoma.
    • --------------------------------------------

    PHARM

    • Bicalutamide preferred over flutamide b/c biclutamide has less hepatic toxicity and taken once a day.
    • ----------------------------------------

    THERA

    • ***COMBO:
    • Androgen receptor antagonist & GnRH
    • receptor analog (to negate S/E of other drug)

    • Rx prostate carcinoma:
    • bicalutamide & a GnRH analog
    • ---------------------------------------

    TOX

    • Bicalutamide preferred over flutamide b/c biclutamide has less hepatic toxicity and taken once
    • a day.

    COMBO w/ GnRH analog to negate S/E
  23. FLUTAMIDE
    &
    NILUTAMIDE
    SAME AS BICALUTAMIDE

    ANDROGEN RECEPTOR ANTAGONIST

    • Competitively
    • block androgen receptors

    Block androgen receptors in hypothalamus →

    Lose feedback inhb of LH secretion →

    Incr plasma levels of LH →

    Incr plasma levels of testosterone

    Rise in testosterone limits effect of anti-androgenic drug →

    • Use bicalutamide & a GnRH analog to Rx prostate
    • carcinoma.
    • --------------------------------------------

    PHARM

    • Bicalutamide preferred over flutamide b/c biclutamide has less hepatic toxicity and taken once a day.
    • ----------------------------------------

    THERA

    • ***COMBO:
    • Androgen receptor antagonist & GnRH
    • receptor analog (to negate S/E of other drug)

    • Rx prostate carcinoma:
    • bicalutamide & a GnRH analog
    • ---------------------------------------

    TOX

    • Bicalutamide preferred over flutamide b/c biclutamide has less hepatic toxicity and taken once
    • a day.

    COMBO w/ GnRH analog to negate S/E
  24. LEUPROLIDE
    GnRH RECEPTOR AGONIST

    Initially stim release of LH & FSH in ♂ & ♀ → initial incr in plasma testosterone levels in ♂

    ***

    If given continuously (non-pulsatile) →

    Pituitary GnRH receptors become desensitized (down-regulated) →

    Decr LH secretion

    • Plasma testosterone suppressed to ~ 10% of normal values w/in 2 weeks
    • ---------------------------------------

    PHARM

    3-4 month depot prep for i.m. injection

    • (GOSERELIN -- im IMPLANT LASTS 3 MONTHS)
    • ----------------------------------------

    THERA

    • 1. Rx prostatic carcinoma:
    • Initial incr in plasma testosterone →

    Can cause a flare-up of prostate tumor activity & symptoms (bone pain from metastases) →

    • GnRH analog given w/ bicalutamide
    • to prevent initial exacerbation

    • ***COMBO:
    • Androgen receptor antagonist & GnRH receptor analog (to negate S/E)

    • 2. Rx endometriosis
    • & uterine fibroid tumors

    • 3. Rx central precocious puberty
    • ----------------------------------------

    TOX

    (not necess to know)

    • In ♂:
    • 1.
    • Hot
    • flushes & sweating

    • 2.
    • Edema

    • 3.
    • Gynecomastia

    4. Decr libido
  25. GOSERELIN
    GnRH RECEPTOR AGONIST

    Initially stim release of LH & FSH in ♂ & ♀ → initial incr in plasma testosterone levels in ♂

    ***

    If given continuously (non-pulsatile) →

    Pituitary GnRH receptors become desensitized (down-regulated) →

    Decr LH secretion

    • Plasma testosterone suppressed to ~ 10% of normal values w/in 2 weeks
    • ---------------------------------------

    PHARM

    im IMPLANT LASTS 3 MONTHS

    • (LEUPROLIDE -- 3-4 month depot prep for i.m.
    • injection)
    • ----------------------------------------

    THERA

    • 1. Rx prostatic carcinoma:
    • Initial incr in plasma testosterone →

    Can cause a flare-up of prostate tumor activity & symptoms (bone pain from metastases) →

    • GnRH analog given w/ bicalutamide
    • to prevent initial exacerbation

    • ***COMBO:
    • Androgen receptor antagonist & GnRH receptor analog (to negate S/E)

    • 2. Rx endometriosis
    • & uterine fibroid tumors

    • 3. Rx central precocious puberty
    • ----------------------------------------

    TOX

    (not necess to know)

    • In ♂:
    • 1.
    • Hot
    • flushes & sweating

    • 2.
    • Edema

    • 3.
    • Gynecomastia

    4. Decr libido
  26. DOXAZOSIN
    &
    TERAZOSIN
    Tx OF BPH

    α1 adrenoreceptors (70% α1A ): abundant in smooth musc of prostate, prostatic capsule, prostatic urethra & bladder neck.

    Block α1 receptors →

    Reversible RELAX of smooth musc →

    Decr urethral resistance to flow →

    • 1.
    • More
    • rapid initiation of micturition (less hesitancy)

    • 2.
    • Greater
    • peak flow rate
    • (no longer “weak” stream)

    • 3.
    • More
    • complete emptying
    • -----------------------------------------------------

    PHARM

    • Terazosin was 1st α antagonist approved
    • for Rx BPH.

    • terazosin =
    • doxazosin in therapeutic & S/E

    • terazosin t1/2β =
    • 12 hours

    • doxazosin t1/2β
    • = 22 hours
    • ------------------------------

    THERA

    • Obstructive
    • symptoms of BPH:

    • 1.
    • urgency: feeling the need to urinate RIGHT NOW

    • 2.
    • hesitancy: cannot initiate stream

    • 3.
    • diminished force of urinary stream: “weak” stream

    • 4.
    • nocturia: excessive night time urination

    ***

    • terazosin =
    • doxazosin in therapeutic & S/E

    • α blocker
    • works FAST:

    • Drugs improve
    • symptoms ≤ 2 weeks!!!

    • Can treat BPH
    • & HTN in the same pt
    • ---------------------------------------

    TOX

    1. Dizziness*

    2. Postural hypotension*

    3. Somnolence

    4. Asthenia: fatigue, loss of energy & strength

    5. Nasal congestion

    6. Peripheral edema

    7. Impotence* failure to ejaculate
  27. TAMSULOSIN
    Tx OF BPH

    • MOA
    • SELECTIVE a-1A ADRENORECEPTOR ANTAGONIST
    • -----------------------------------------

    PHARM

    • t1/2 = 12-15 hrs
    • ----------------------------------------

    THERA

    • AS EFFECTIVE AS TERAZOSIN & DEOXAZOSIN
    • -----------------------------------------

    TOX

    • 1.
    • Less dizziness
    • & orthostatic hypotension than terazosin & doxazosin

    • 2.
    • More
    • ejaculatory dysfunction than terazosin & doxazosin (b/c incr α1A receptor selectivity)
    • ·
    • Failure
    • to ejaculate
    • ·
    • Decr
    • volume of ejaculate
    • ·
    • Retrograde
    • ejactulation
  28. FINASTERIDE
    Tx OF BPH

    • 5α-reductase converts testosterone to DHT
    • ·
    • Type 1: liver & skin
    • ·
    • Type 2: prostate

    DHT respb for prostatic hypertrophy.

    ***

    Selectively inhb type 2 form of 5α-reductase

    Inhb 5α-reductase →

    • Prevent conversion of testosterone to DHT →
    • 1. Plasma testosterone levels incr by 10%

    2. Plasma DHT levels decr by 70%

    3. Prostate gland conc of DHT decr > 70%

    • 4. Plasma LH is NOT changed
    • ----------------------------------------

    PHARM

    • BPH
    • ·
    • Avg
    • decr in prostate size ~25%
    • (larger prostate, greater response)
    • ·
    • Decr
    • prostate size associated w/ decr in BPH symptoms
    • ·
    • Decr
    • prostate size noted by 3 mo & shrinkage continues for next 1-2
    • yrs
    • ·
    • Decr
    • prostate size maintained as long as pt continues to take drug
    • ·
    • Decr
    • need for a TURP (transurethral
    • resection of the prostate)

    • Male pattern baldness:
    • ·
    • Inhb 5α-reductase in hair follicles →
    • prevent hair loss
    • ·
    • Used
    • w/ topical preparation of arterial
    • vasodilator minoxidil to treat
    • alopecia
    • --------------------------------------------

    THERA

    1. BPH

    • Need new baseline PSA after 1 year Rx BPH w/ 5α-reductase
    • inhibitor

    • 2. Male pattern baldness
    • ----------------------------------------

    TOX

    • 1.
    • Impotence
    • (decr volume of ejaculate)

    • 2.
    • Decr libido

    • Need new baseline
    • PSA after 1 year Rx BPH w/ 5α-reductase inhibitor

    ***

    finasteride (5 mg, p.o.)

    Decr serum [PSA] by 50% →

    Pt need periodic rectal exams to screen for prostatic cancer.

    finasteride (1 mg, p.o.)

    Does NOT decr PSA

    ***

    • dutasteride (Rx
    • 3 mo) Decr serum [PSA]
    • by 40%

    • dutasteride (Rx
    • 6 - 12 mo) Decr serum [PSA]
    • by 50%
  29. DUTASTERIDE
    Tx OF BPH

    INH BOTH FORMS OF 5a-REDUCTASE

    • (rest same as finasteride)
    • ----------------------------------------

    PHARM

    • BPH
    • ·
    • Avg
    • decr in prostate size ~25%
    • (larger prostate, greater response)
    • ·
    • Decr
    • prostate size associated w/ decr in BPH symptoms
    • ·
    • Decr
    • prostate size noted by 3 mo & shrinkage continues for next 1-2
    • yrs
    • ·
    • Decr
    • prostate size maintained as long as pt continues to take drug
    • ·
    • Decr
    • need for a TURP (transurethral
    • resection of the prostate)

    • Male pattern baldness:
    • ·
    • Inhb 5α-reductase in hair follicles →
    • prevent hair loss
    • ·
    • Used
    • w/ topical preparation of arterial
    • vasodilator minoxidil to treat
    • alopecia
    • --------------------------------------------

    THERA

    1. BPH

    • Need new baseline PSA after 1 year Rx BPH w/ 5α-reductase
    • inhibitor

    • 2. Male pattern baldness
    • ----------------------------------------

    TOX

    • 1.
    • Impotence
    • (decr volume of ejaculate)

    • 2.
    • Decr libido

    • Need new baseline
    • PSA after 1 year Rx BPH w/ 5α-reductase inhibitor

    ***

    finasteride (5 mg, p.o.)

    Decr serum [PSA] by 50% →

    Pt need periodic rectal exams to screen for prostatic cancer.

    finasteride (1 mg, p.o.)

    Does NOT decr PSA

    ***

    • dutasteride (Rx 3 mo) Decr serum [PSA]
    • by 40%

    • dutasteride (Rx 6 - 12 mo) Decr serum [PSA]
    • by 50%
  30. DESMOPRESSIN
    (DDAVP)
    Tx OF VOIDING DYSFUNCTION


    Long acting synthetic analog of AVP (ADH)

    • Selective for V2 receptors found in principal
    • cells of late DT & CD
    • -------------------------------------

    PHARM

    Duration of action = 6-20 hours

    Given by nasal spray at bedtime to enhance renal absorption of H2O → decr urinary volume

    • Allergic rhinitis or nasal congestion (URI) → slow drug absorption
    • ----------------------------------------

    THERA

    • *Nocturnal enuresis in children “bedwetting”:
    • --Decr nocturnal production of urine (antidiuretic)

    Given by nasal spray at bedtime to enhance renal absorption of H2O → decr urinary volume

    Allergic rhinitis or nasal congestion (URI) → slow drug absorption
  31. ALOPROSTADIL
    Tx OF ERECTILE DYSFUNCTION

    • PGE1 RECEPTOR AGONIST
    • ------------------------------------
    • PHARM

    • Topical
    • ·
    • Muse (urethral suppository): Onset
    • 5-10 min. Acts for 30-60 min
    • ·
    • Topiglan (gel) & Alprox-TD (cream): Applied to glans. Onset in 30-40 mins

    • Injection: Onset: 5 min. Acts for 1-1.5 hours
    • --------------------------------------

    THERA

    TOPICAL OR INJECTION INTO CORPUS CAVERNOSA

    USED FOR Pts WHO DO NOT RESPOND TO SILDENAFIL
  32. SILDENAFIL
    Tx OF ERECTILE DYSFUNCTION

    • SELECTIVE PDEase TYPE 5 INH
    • ----------------------------------

    PHARM

    ONSET: 30-60 min

    ACTS FOR 4-5 hrs

    • TAKE 1 hr BEFORE SEX --> ERECTION LASTS 0.5 - 2 hrs
    • ----------------------------------

    TOX

    • 1.
    • “smurf” vision & impairment of blue-green color discrimination:

    From partial blockade of PDEase type 6 b/c cGMP is involved in signal transduction in cones of retina

    • 2.
    • NAION (non-arteritic ischemic optic neuropathy)

    From decr’d blood flow to optic nerve. Serious, but reversible S/E

    • 3. headache
    • & flushing

    Drug interactions:

    --Poss → severe hypotension → chest pain, MI, or ischemic stroke

    • 1.
    • Do NOT use any nitrate in presence of PDEase
    • type 5 inhibitor.

    2. Do NOT use PDEase type 5 inhibitor in pts taking α-blockers for BPH (terazosin, doxasin).
  33. VARDENAFIL
    Tx OF ERECTILE DYSFUNCTION

    • PHARM
    • --ONSET 60 mins
    • --ACTS FOR 4-5 hrs
    • -----------------------------------

    TOX

    • 1.
    • “smurf” vision & impairment of blue-green color discrimination:

    From partial blockade of PDEase type 6 b/c cGMP is involved in signal transduction in cones of retina

    • 2.
    • NAION (non-arteritic ischemic optic neuropathy)

    From decr’d blood flow to optic nerve. Serious, but reversible S/E

    • 3. headache
    • & flushing

    Drug interactions:

    --Poss → severe hypotension → chest pain, MI, or ischemic stroke

    • 1.
    • Do NOT use any nitrate in presence of PDEase
    • type 5 inhibitor.

    2. Do NOT use PDEase type 5 inhibitor in pts taking α-blockers for BPH (terazosin, doxasin).
  34. TADALAFIL
    Tx FOR ERECTILE DYSFUNCTION

    • PHARM
    • --ONSET 30-45 mins
    • --ACTS FOR 24 hrs
    • -------------------------------------

    TOX

    • 1.
    • “smurf” vision & impairment of blue-green color discrimination:

    From partial blockade of PDEase type 6 b/c cGMP is involved in signal transduction in cones of retina

    • 2.
    • NAION (non-arteritic ischemic optic neuropathy)

    From decr’d blood flow to optic nerve. Serious, but reversible S/E

    • 3. headache
    • & flushing

    Drug interactions:

    --Poss → severe hypotension → chest pain, MI, or ischemic stroke

    • 1.
    • Do NOT use any nitrate in presence of PDEase
    • type 5 inhibitor.

    2. Do NOT use PDEase type 5 inhibitor in pts taking α-blockers for BPH (terazosin, doxasin).
  35. CYTOKINES FROM ANTIGEN PRESENTING CELLS
    IL-1 & IL-6

    IL-1 ACT TH0 HELPER T-CELLS

    IL-6 ACT TH2 HELPER T-CELLS, B-CELL LYMPHs, AND PLASMA CELLS
  36. CYTOKINES SECRETED BY TH0 CELLS
    ACTIVATED TH0 CELLS SECRETE IL-2 --> T-CELL PROLIF AND FURTHER PROD OF IL-2 AND TH0

    IL-2 RELEASED FROM ALL TH-CELLS IN EARLY STAGES
  37. CYTOKINES SECRETED BY TH1 CELLS
    IL-2, INF-g, TNFb

    • INF-g AND TNFb:
    • --ACTIVATE MACROs, NK CELLS, AND CYTOTOXIC T-CELLS

    --INC EXPRESSION OF ADHESION MOLS IN VASCULAR ENDO OF GRAFT --> MORE LIKELY HOST LEUKOs INVADE

    --INFg INDUCE PARENCHYMAL CELLS OF GRAFT TO EXPRESS MHC-II (RARE) --> ENHANCED EXPRESSION OF FOREIGN MHC-II INC STIM OF RECIPIENT'S IMMUNE SYSTEM AND PROVIDES MORE TARGETS WITHIN GRAFT FOR Ab PROD BY HOST
  38. CYTOKINES SECRETED BY TH2 CELLS
    IL-2, 4, 5, 6, 10

    STIM PROLIF OF B-CELLS AND DEV OF Ab SECRETING PLASMA CELLS

    TH2 CONTROLS HUMORAL IMMUNITY

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