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Pharm > Test 3 > Flashcards

Test 3 Flashcards

1
Q

Proximal Convoluted Tubule

A

Highly permeable to H2O and reabsorbs 65% of NaCl

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2
Q

Thin Descending Limb of Loop of Henle

A

Highly permeable to H2O but impermeable to NaCl and Urea (Concentrating Segment)

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3
Q

Thin Ascending Limb of the Loop of Henle

A

Passively reabsorbs NaCl but impermeable to H2O

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4
Q

Thick Ascending Limb of the Loop of Henle

A

Actively reabsorbs most of the NaCl absorbed in loop, impermeable to H2O (diluting segment), and contains macula densa located between afferent and efferent arterioles.

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5
Q

Tubuloglomerular feedback

A

Signal sent from macula densa to afferent arteriole of same nephron causing vasoconstriction when amount of NaCL leaving the Loop is too high. Vasoconstriction –> decrease GFR

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6
Q

Distal Convoluted Tubule

A

Actively transports NaCl but is impermeable to H2O (diluting segment)

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7
Q

Collecting Duct

A

Fine control of ultra filtrate composition, controlled by aldosterone (increased NaCl and H2O reabsorption) and ADH (increased H2O reabsorption)

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8
Q

Chloride Reabsorption

A

Generally follows Na, Symport with K+ in proximal tubule and thick ascending limb, Antiport with Na+/HCO3- in proximal tubule, and Cl- channels in thick ascending limb, DCT, and Collecting Duct

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9
Q

Renal handling of Potassium

A

80-90% absorbed in proximal tubule via diffusion, paracellular pathways are used in thick ascending limb, DCT and Collecting duct K+ secretion by a conductive pathway.

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10
Q

Renal Handling of Calcium

A

70% reabsorbed by proximal tubule but passive diffusion through a paracellular route, 25% is absorbed by thick ascending limb, remaining 5% is reabsorbed in DCT by transcellular pathway.

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11
Q

Renal Handling of Inorganic Phosphate

A

Largely reabsorbed by proximal tubule (80%)

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12
Q

Renal Handling of Magnesium

A

Bulk reabsorbed in Thick ascending limb via paracellular pathway, 20-25% reabsorbed in proximal tubule, 5% is by DCT and collecting duct

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13
Q

Relationship between sodium reabsorption and potassium secretion in the Collecting Duct

A

More Na+ reabsorbed = More potassium excreted, More sodium in collecting duct –> more compensation –> more K+ excretion (hypokalemia).

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14
Q

Targets of Diuretics

A

Diuretics target Na+ transporters and channels on the luminal side of tubules –> more Na+ excretion in urine (natriuresis) –> More H2O excretion in urine (Diuresis)

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15
Q

Prototype Carbonic Anhydrase Inhibitor

A

Acetazolamide

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16
Q

Site of action of Carbonic Anhydrase Inhibitors

A

Proximal Tubule

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17
Q

Mechanism of Action of Carbonic Anhydrase Inhibitors

A

Competitive inhibitors of luminal and cytosolic carbonic anhydrase, Causes decreased reabsorption of HCO3-, decreased secretion of H+ –> decreased Na+ reabsorption.

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18
Q

Efficacy of Carbonic Anhydrase inhibitors

A

Modest because distal segments of nephron can compensate for increased Na+ concentration.

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19
Q

Renal hemodynamic effects of Carbonic Anhydrase inhibitors

A

-Because of increased Na+ concentration at macula densa, afferent vasoconstriction –> decreased GFR

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20
Q

Adverse effects of Carbonic Anhydrase Inhibitors

A

-Hypokalemia (potassium wasting) due to compensation by Na+/K+ exchange in distal nephron -Urinary alkalization due to increased HCO3- excretion –> metabolic acidosis. -Renal stone formation b/c Ca2+ is insoluble at alkaline pH

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21
Q

Therapeutic Uses of Carbonic Anhydrase Inhibitors

A

-Rarely used as diuretic -Open-angle glaucoma -Altitude sickness -Epilepsy

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22
Q

Urinary Electrolyte changes due to Carbonic Anhydrase inhibitor (Acetazolamide)

A

-Increase pH due to increased HCO3- excretion -Increased Na+ excretion due to decreased H+/Na+ antiport action -Increased K+ excretion due to increased K+/Na+ antiport action caused by increased [Na+] in distal nephron

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23
Q

Prototype Loop Diuretic

A

Furosemide

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24
Q

Loop Diuretic Site of Action

A

Thick ascending limb of Loop of Henle

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25
Q

Loop Diuretic Mechanism of Action

A

Inhibits Na+ K+ 2 Cl- transporter, abolishes transepithelial potential gradient that drives paracellular Mg 2+ and Ca 2+ reabsorption leading to increased Mg and Ca excretion in urine

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26
Q

Loop Diuretic Effects on Tubuloglomerular Feeback

A

-Inhibit TGF because they inhibit salt transport in macula densa, so kidneys don’t “see” excess Na+.

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27
Q

Renal Hemodynamic effects of Loop Diuretics

A

-Increase in RBF (prostaglandin mediated effect -Stimulates Renin release via SNS activation due to volume depletion -Increases venous capacitance and decreases left ventricular filling pressure

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28
Q

Pharmacokinetics of Loop Diuretics

A

-Highly protein bound (must use transporter) -Uses OAT 1 for apical deliverance (OAT 1 also used by NSAIDs) -Short elimination T1/2

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29
Q

Therapeutic Uses of Loop Diuretics

A

-Pulmonary edema -Congestive heart failure -Hypercalcemia

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30
Q

Adverse Effects of Loop Diuretics

A

-Hypo: Natremia, Kalemia, Calcemia -Ototoxicity -NSAIDs reduce diuretic efficacy -Hyperglycemia (use caution with sulfonylureas

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31
Q

Prototype Na+ Cl- Symport Inhibitor

A

Chlorothiazide and Chlorthalidone

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32
Q

Site of action of Na+ - Cl- symport inhibitors

A

Distal convoluted tubule

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33
Q

Mechanism of action of Na+ - Cl- Symport inhibitors

A

Inhibits Na+ - Cl- symporter, also weak carbonic anhydrase inhibitor, Efficacy is substantially reduced with low GFR.

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34
Q

Effects of Na+ - Cl- Symport inhibitors on Urinary electrolyte concentrations

A

-Decreases Ca 2+ due to development of transepithelial potential gradient -Increases Na+, K+, and Cl- excretion in urine. -Reduces ability of kidney to dilute urine during diuresis

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35
Q

Pharmacokinetics of Chlorothiazide (Na-Cl symport inhibitor)

A

-Longer half life than loop diuretics -Delivered to lumen by organic anion transporter

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36
Q

Therapeutic uses of Chlorothiazide

A

-1st line for mild to moderate hypertension -Mild Edema -Nephrogenic Diabetes insipidus (paradoxical effect decrease Plasma volume leads to decreased GFR which leads to increased proximal tubule absorption.

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37
Q

Adverse effects of Na+ - Cl- Symport inhibitors

A

Hypo: Kalemia, natremia Hyper: Glycemia, uricemia, and lipidemia ED NSAIDs reduce efficacy

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38
Q

Prototype Potassium Sparing Diuretics

A

-Triamterene and Amiloride (ENaC inhibitors) -Spironolactone and Eplerenone (Aldosterone Antagonists)

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39
Q

Mechanism of Action of Potassium Sparing Diuretics

A

-ENaC inhibitors: Block epithelial Na+ channels on the apical membranes of principal cells -Aldosterone Antagonists: Block cytosolic mineralocorticoid receptors to reduce expression of aldosterone induced proteins -Both types abolish transepithelial gradient that causes K+ and H+ secretion in to kidney lumen.

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40
Q

Therapeutic Uses

A

-Not for Diuretic Effect -Used with other K+ wasting diuretics to prevent hypokalemia -ENaC inhibitors used to treat Liddle Syndrome and Cystic fibrosis -Aldosterone Antagonists used for primary hyperaldosteronism, hepatic cirrhosis, and CHF

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41
Q

Adverse Effects

A

-Hyperkalemia (use with caution with ACE inhibitors and NSAIDs -Spironolactone: Affinity for steroid receptors (gynecomastia, impotence, hirsutism, decreased libido) -Eplerenone: Lower incidence of progesterone related effects due to high specificity

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42
Q

Maximum time after onset of flu symptoms to start chemotherapy

A

48 hrs

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43
Q

Prototype Adamantane

A

Amantadine

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44
Q

Amantadine Mechanism of Action

A

Blocks M2 ion channel in influenza A. Stops influx of proteins and interferes with viral uncoating.

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45
Q

Amantadine Resistance

A

Nearly 100% but may need to be used in future with evolution of influenza A

46
Q

PK Amantadine

A

Orally available and well absorbed from GI tract. Eliminated by renal excretion.

47
Q

Therapeutic uses of Amantadine

A

-Influenza A treatment when used with Neuraminidase inhibitors. -Parkinson’s Disease

48
Q

Adverse Reactions of Amantadine

A

-Contraindicated in Pregnancy -Drug interactions with Anti-cholinergics -CNS effects

49
Q

Prototype Neuraminidase Inhibitor

A

Oseltamivir

50
Q

Oseltamivir Structure & MOA

A

-Analog of Neuramic Acid -Competitive inhibitor of neuraminidase, interferes with replication and spread of Influenza A & B by preventing release from infected cells.

51
Q

Oseltamivir PK & Resistance

A

-Orally available prodrug that is metabolized –> active carboxylate in Liver and excreted as carboxylate from kidneys -Resistance is variable in seasonal flu, some resistance seen in H5N1.

52
Q

Zanamivir

A

-Low oral bioavailability oral inhalation neuraminidase inhibitor. -SHOULDN’T be used in people with ASTHMA or COPD

53
Q

Drugs used to treat CMV (Herpes Virus)

A

-Ganciclovir (Nucleoside analog) -Cidofovir (Nucleotide analog)

54
Q

Drugs used to Treat HSV and VZV

A

Acyclovir and Valacyclovir

55
Q

Prototype Nucleoside analog for HSV and VZV

A

Acyclovir

56
Q

Acyclovir Structure and Spectrum

A

-Acyclic guanine nucleoside prodrug w/o 3’-OH -HSV >> VZV >>>> CMV

57
Q

Acyclovir MOA

A

-Selectively –> acyclo-GMP (Viral thymidine Kinases in cytoplasm of infected cells) -Host Cell Kinases acyclo-GMP –> acyclo GTP -Acyclo-GTP –> Nucleus where it is inserted in to Viral DNA by viral DNA polymerase and causes chain termination -Competitive inhibition of Viral DNA polymerase (100-fold greater affinity for viral DNA poly than Mammalian)

58
Q

Acyclovir Resistance & Therapeutic Uses

A

-Resistance is by Viral TK deficiency, major concern in immunocompromised receiving prolonged therapy. -HSV (genitial, Herpetic gingivostomatitis, prophylaxis of mucocutaneous HSV in immunosuppressed patients, HSV encephalitis) -VZV (Varicella infections in children and adults, Elderly and immunocompromised with HZV)

59
Q

Valacylovir

A

-L-Valyl ester prodrug that has 5-fold greater oral bioavailability -converted to acyclovir by liver in first pass hepatic metabolism

60
Q

Adverse effects of Acyclovir

A

-neurotoxicity: tremor, myoclonus, seizures, and extrapyramidal signs -Reversible Renal Dysfunction: Crystalline nephropathy due to precipitation of drug

61
Q

Prototype NucleoSIDE analog for CMV

A

Ganciclovir

62
Q

Ganciclovir: Structure and MOA

A

-Acyclovir Analog but WITH 3’-OH -Converted to mono PO4 by VIRAL kinase (CMV UL97) -HOST cell Kinases –> tri-PO4 -Inhibits Viral DNA polymerase but no chain termination because of 3’-OH -Selectivity of CMV is much less than acyclovir for HSV.

63
Q

Ganciclovir PK

A

-Orally effective but low bioavailability. Valganciclovir has a much higher oral bioavailability.

64
Q

Ganciclovir Therapeutic Uses & Adverse effects

A

-CMV Retinitis in immunocompromised patients -Prevention of CMV in transplant patients. -Myelosupression treated with G-CSF -CNS effects (Headache, fever, convulsions and behavior changes)

65
Q

Prototype NucleoTIDE analogs for CMV

A

Cidofovir

66
Q

Cidofovir Structure and MOA

A

-Cytidine nucleoTIDE analog -DOESN’T use Viral TK, converted to active di-PO4 by host cell kinases -Inhibits viral DNA polymerase

67
Q

Cidofovir: PK

A

-Given IV -Prolonged T 1/2 -Renal glomerular filtration given with probenecid to block OAT-1

68
Q

Cidofovir Therapeutic Use

A

-CMV retinitis in AIDS patients, alternative to ganciclovir and foscarnet

69
Q

Cidofovir Adverse effects

A

-Nephrotoxicity (PCT dysfunction, major dose limiting toxicity, probenecid and saline reduce risk) -Neutropenia

70
Q

Prototype Non-Nucleoside analogs for drug resistant HSV and CMV

A

Foscarnet

71
Q

Foscarnet: Structure and Function

A

-Phosphorylated Analog of Formic Acid -BROAD SPECTRUM: ALL HERPES VIRUSES and HIV -Inhibits HSV DNA polymerase -Inhibits HIV RT -NOT phosphorylated by VIRAL or HOST kinases.

72
Q

Foscarnet PK

A

-Given IV -Taken up slowly and not metabolized -80% unchanged excretion in Urine

73
Q

Foscarnet: Therapeutic Uses

A

-CMV retinitis (including Ganiciclovir resistant) In AIDS patients -Acyclovir Resistant HSV and VZV infections

74
Q

Foscarnet Adverse effects

A

-Nephrotoxicity -Pronounced Electrolyte disturbances (symptomatic hypocalcemia)

75
Q

How is the efficacy of Antiviral treatment measured?

A

Sustained Viral Response (SVR): Absence of HCV RNA by PCR 24 weeks after stopping treatment.

76
Q

Ribavirin: Structure and antiviral activity

A

-Purine Nucleoside analog prodrug -Broad spectrum activity against DNA and RNA viruses

77
Q

Ribavirin: MOA and PK

A

-MOA: Converted to mono, di, and tri phosphates by HOST CELL KINASES, Inhibits IMP dehydrogenase –> decreased GTP, Causes lethal mutation in RNA viruses -PK: Given Orally (HCV) or via Inhalation (RSV), LONG half life and High Vd, Hepatic metabolism and renal excretion

78
Q

Ribavirin: Therapeutic Uses and Adverse RXNS

A

-Given orally in fixed does with IFN for chronic HCV, Given via inhaler for RSV -Hemolytic anemia and contraindicated in pregnancy.

79
Q

Interferons: Antiviral spectrum and MOA

A

-Broad Spectrum -Bind receptors on host cells that activate JAK-STAT pathway that leads inhibits viral protein synthesis, maturation, and release, Stimulates host immune system by up regulating MHC I and II

80
Q

Pegylated INF-alpha 2 A

A

-INF- alpha 2 a with a polyethylene glycol residue added to improve SVR and half life.

81
Q

IFN therapeutic uses

A

-Chronic HCV and HBV, genital warts (administered directly on to lesions), Some cancers.

82
Q

IFN Adverse effects

A

-Flu like symptoms that decrease with time. -Depression (black box) -Myelosuppression

83
Q

Direct acting Antivirals for HCV

A

-Simeprevir: (Protease inhibitor) -Sofosbuvir: Nucleotide prodrug

84
Q

Simeprevir: MOA and Resistance

A

-MOA inhibits HCV viral protease needed for viral maturation -Resistance is high if used alone

85
Q

Simeprevir: PK and adverse reactions

A

-Orally once per day with Ribavirin/IFN -Contraindicated during pregnancy and CYP3A4 related drug interactions.

86
Q

Sofosbuvir: MOA and efficacy

A

-Nucleotide prodrug that is converted to active triphosphate, inhibits viral RNA polymerase and chain terminator -Efficacy across all HCV genomes

87
Q

Prototype Nucleoside reverse transcriptase inhibitor

A

Zidovudine (AZT)

88
Q

Zidovudine: Structure and MOA

A

-Structure: Thymidine Analog (Prodrug) -MOA: Converted by host cell kinases to active triphosphate competes with endogenous TTP for RT binding site and causes chain termination

89
Q

Zidovudine: Resistance and Combination drug

A

-Patients develop resistance if drug is used alone. Prolonged mono therapy also promotes cross resistance to other NRTIs -Combined with Lamivudine to decrease viral load and prevent development of resistance

90
Q

Zidovudine: PK and Therapeutic Uses

A

-Orally available and widely distributed, Eliminated by hepatic glucuronidation -Used with Lamivudine for HIV infection, Prevention of HIV transmission Mother –> Child, Prophylaxis in healthcare workers

91
Q

Zidovudine: Adverse effects

A

-Lactic acidosis and hepatic steatosis

92
Q

Lamuvidine

A

-Lower toxicity than Zidovudine and also used to treat HBV

93
Q

Emtricitabine

A

Lamivudine analog with once a day dosing

94
Q

Tenofovir

A

NucleoTIDE analog also treats HBV

95
Q

Non-Nucleoside Reverse transcriptase Inhibitors

A

-Efavirenz

96
Q

Efavirenz: Structure and MOA

A

Structure: Not related to endogenous nucleosides MOA: Allosteric inhibitor of HIV-1 RT, NO phosphorylation required, DOESN’T inhibit host cell polymerases

97
Q

Efavirenz: Resistance and PK

A

-Resistance: Highly susceptible due to single AA mutations in RT, HIV-2 is intrinsically resistant -PK: Orally, Cleared by CYPs, Can be given in once daily dosage

98
Q

Efavirenz: Therapeutic Uses and Adverse Effects

A

-Therapeutic Uses: HIV-1 infection used once daily in fixed dose with Tenofovir and Emtricitabine, EFFECTIVE FOR THOSE WHO HAVE FAILED PREVIOUS ANTIRETROVIRAL THERAPIES NOT CONTAINING NNRTI -CNS symptoms, Rash (can be life threatening), Teratogen

99
Q

Nevirapine

A

-Same uses as efavirenz but boxed warning for liver toxicity

100
Q

Prototype Protease Inhibitor

A

-Lopinavir and Ritonavir fixed dose combo

101
Q

Lopinavir and Ritonavir: MOA and PK

A

-Competitive inhibition of HIV protease, prevents cleavage of gag and pol precursor poly proteins, Human proteases not inhibited -PK: Orally available and well absorbed, Ritonavir only boosts lopinavir activity by inhibiting CYP mediated clearance (CYP 3A4)

102
Q

Lopinavir and Ritonavir: Adverse effects

A

-GI intolerance and lipodystrophy syndrome with long term use

103
Q

Atazanavir

A

Protease inhibitor with same function and Lopinavir and Ritonavir, don’t use with PPI

104
Q

Prototype Fusion inhibitors

A

-Enfuvirtide

105
Q

Enfuvirtide: Structure and MOA

A

-36 AA synthetic peptide mimic of GP-41 -MOA: Bind HIV GP-41 and prevents HIV envelope fusion with CD4

106
Q

Enfuvirtide: PK and Therapeutic uses

A

PK: SC 2x/day Therapeutic Uses: Added to existing regimens when there is evidence of replication despite continued therapy

107
Q

Enfuvirtide: Adverse effects

A

-Injection site reactions, elevated risk of bacterial pneumonia

108
Q

Maraviroc:

A

-Block chemokine CCR-5 Co-receptor and prevents binding of Viral GP-120 (only RV to target host protein) -Used only in CCR-5 Tropic infections

109
Q

Prototype Intergrase Inhibitor:

A

Raltegravir

110
Q

Raltegravir: MOA and Therapeutic uses

A

-Inhibits HIV Integrase, human DNA doesn’t undergo this process -HIV infections in HAART

Pharm (8 decks)

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