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233 2nd midterm > Review 2 > Flashcards

Review 2 Flashcards

1
Q

what are 3 types of iron and vitamin deficiency anemias?

A

– Hypochromic, microcytic anemia (small red cells with low hemoglobin; caused by chronic blood loss giving rise to iron deficiency)
– Megaloblastic anemia (large red cells, few in number); caused by a deficiency of Vit B12 or folic acid
– Pernicious anemia (fewer normal-sized red cells, each with a normal hemoglobin content); caused by a deficiency of Vit B12 due to defect in intrinsic factor

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2
Q

causes of anemia

which nutrients necessary for haemopoiesis might be deficient?

A

– iron
– folic acid and vitamin B 12
– pyridoxine (vit B6) and vitamin C (important for iron abs)

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3
Q

what are 2 categories for treating anemia?

A

hematinic agents

hematopoietic growth factors

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4
Q

name 2 hematinic agents

A
  • Iron

- Folic acid and Vit B12

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5
Q

name 4 Hematopoietic Growth Factors

A
  • Erythropoietin
  • Granulocyte Colony-Stimulating Factor (G-CSF)
  • Granulocyte-Monocyte Colony-Stimulating Factor (GM-CSF)
  • Megakaryocyte (Thrombopoietic) Growth Factors
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6
Q

Hematinic agents: Iron

which form of iron is absorbed?
where is it absorbed?
what is a transport protein for iron?

A

• Ferric iron (Fe3+) must be converted to ferrous iron (Fe2+, reduced form) for absorption (by ferric reductase enzyme) in the GI tract.
• Absorption involves active transport into mucosal cells in the duodenum and jejunum (the upper ileum), from where it can be transported into the plasma and/or stored intracellularly as ferritin.
• Total body iron is controlled exclusively by absorption; in iron deficiency, more is transported into plasma than is stored as ferritin in jejunal mucosa.
• Iron that is released is transported by transferrin (the
transport protein).
• Transferrin delivers the iron to either the liver for storage or to bone marrow for further hemoglobin and RBC production

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7
Q

Hematinic agents: Iron

name oral and IV common drugs

A

Iron formulations are used for treatment of iron deficiency

Oral: ferrous sulfate, ferrous fumarate, ferrous gluconate, polysaccharide-iron complex
IV: iron dextran, sodium ferric gluconate, iron sucrose

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8
Q

Hematinic agents: Iron

side effects

A

• Gastrointestinal disturbances.
• Severe toxic effects occur if large doses are ingested;
such acute poisoning can be treated with desferrioxamine, an iron chelator as can chronic iron overload in diseases such as thalassemia.

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9
Q

when does iron overload occur? (2)

A

Iron overload occurs in chronic hemolytic anaemias
requiring frequent blood transfusions, such as;
- Thalassaemias (a large group of genetic disorders of globin chain synthesis)
- Hemochromatosis (a genetic iron storage disease with increased iron absorption, resulting in damage to liver, islets of Langerhans, joints and skin).

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10
Q

how to treat iron overload?

3

A
  • Desferrioxamine: form a complex with ferric iron which, unlike unbound iron, is excreted in the urine.
  • Desferrioxamine is not absorbed from the gut. Therefore, it must be given by slow SC infusion. For acute iron overdose, it is given IM or IV
  • Deferiprone is an orally absorbed iron chelator, used as an alternative treatment for iron overload in patients who are unable to take desferrioxamine.
  • Deferasirox is similar, but can cause GI bleeding
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11
Q

Hematinic agents: Folic Acid and Vitamin B12

what is the role of folic acid and Vit B12

A

Prototype: B9: Folic acid; B12: Cyanocobalamin,
hydroxocobalamin
• Vitamin B12 and folic acid play key roles in DNA synthesis. Active forms of folic acid serve as enzyme cofactors that play key roles in the synthesis of purines and pyrimidines, as well as amino acids, in the body.
• A deficiency of folic acid or B12 affect cells that are actively dividing, such as the cells of the bone marrow, which are involved in erythropoiesis. Therefore, the deficiencies of these vitamins is anemia.
• Specifically, B12 deficiency results in abnormal DNA replication, which prevents cells from maturing properly, leading to production of large, dysfunctional RBC precursors (megaloblasts) that do not leave the marrow, or abnormal cells that do leave the marrow.
• B12 deficiency can also affect the nervous system, causing inflammation, demyelination, and neuronal cell death

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12
Q

Hematinic agents: Folic Acid and Vitamin B12

MOA?

A
  • Folic acid: Reduction of folic acid, catalyzed by dihydrofolate reductase in two stages yields dihydrofolate (FH 2 ) and tetrahydrofolate (FH 4 ), co-factors which transfer methyl groups (1- carbon transfers) in several important metabolic pathways.
  • FH 4 is essential for DNA synthesis.
  • B12: involves conversion of both methyl-FH 4 to FH 4 and homocysteine to methionine

see diagram:

  • Convert homocysteine to methionine important for DNA synthesis B12 important for conversion of methyl tetrahydrofolate to and tetrahydrofolate (methyl FH4 tp FH4)
  • Thymidylate synthase convert methylene dUMP to dTMP or DNA synthesis
  • Reduction of folic acid yields dihydrofolate and tetrahydrofolate
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13
Q

Hematinic agents: Folic Acid and Vitamin B12

indications for Vitamin B12

A
  • Pernicious anemia

* Megaloblastic and macrocytic anemias caused by poor B12 absorption

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14
Q

Hematinic agents: Folic Acid and Vitamin B12

Folic Acid

A
  • Megaloblastic and macrocytic anemias
  • Prevention of neural tube defects in neonates (give to pregant women)
  • Adjunct to methotrexate to prevent methotrexate toxicity (can be used for alopecia)
  • Pernicious anemia (combined with B12)
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15
Q

Hematopoietic Growth Factors: Erythropoietins

MOA continued
where does EPO bind a receptor and what types of effects will happen

A
  • Patients with a deficiency of erythropoietin will be anemic. This occurs commonly in patients with renal failure.
  • Once released, erythropoietin binds to a receptor on the surface of committed erythroid progenitor cells in the bone marrow.
  • Binding to this receptor mediates a variety of intracellular effects through tyrosine kinases, including the inhibition of apoptosis.
  • Inhibiting apoptosis prevents RBCs from dying at an early stage of development. Erythropoietin also promotes proliferation through Janus protein kinase-2 (JAK2) pathways

More cell proliferation, no death of RBCs

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16
Q

Hematopoietic Growth Factors: Erythropoietins

Indications

A
  • Anemia
  • In advanced renal failure (can’t make it)
  • Associated with chemotherapy and acquired immunodeficiency syndrome (AIDS)
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17
Q

Hematopoietic Growth Factors: Erythropoietins

AE (4)

A

• Iron deficiency: If iron stores cannot keep up with
erythropoiesis, patients may develop a functional iron
deficiency. Patients need an iron supplement.
When you make RBC it has hemoglobin which needs iron - will take plasma iron

• Thrombosis: particularly in patients on dialysis. It is
recommended that these patients receive anticoagulant therapy as a prophylactic measure.
• Hypertension: Although increased hematocrit can lead to increased blood pressure, the mechanism is believed to be more likely a result of the interaction between erythropoietin and vasoactive factors such as angiotensin II.
• Seizures: Seizures have been reported in dialysis patients receiving epoetin alfa

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18
Q

Hematopoietic Growth Factors: Colony Stimulating Factors

function?
2 prototypes

A

Colony-stimulating factors (CSFs) are agents that stimulate the production of neutrophils and monocytes
• Granulocyte Colony-Stimulating Factor (G-CSF):
filgrastim, lenograstim, pegfilgrastim
- astim

• Granulocyte-Monocyte Colony-Stimulating Factor (GMCSF): sargramostim
- ostim

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19
Q

Hematopoietic Growth Factors: Colony Stimulating Factors

MOA?

A

• The CSFs work by binding to receptors on myeloid
progenitor cells. These are cells in the bone marrow that make RBCs, platelets, granulocytes, and monocytes. The actions of these receptors are mediated through the Janus protein kinase/signal transducers and activators of transcription (JAK/STAT) pathway.
• G-CSFs stimulate proliferation and differentiation only of progenitors commited to becoming neutrophils.
• GM-CSFs stimulate the production of neutrophils and
monocytes, as well as the actions (phagocytosis,
superoxide production, and cell-mediated toxicity) of
neutrophils, monocytes, and eosinophils

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20
Q

Hematopoietic Growth Factors: Colony Stimulating Factors

Indications

A

• Adjunct to myelosuppressive chemotherapy
• Severe chronic neutropenia
• Prevention and treatment of neutropenia in human
immunodeficiency virus (HIV) infection

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21
Q

Hematopoietic Growth Factors: Colony Stimulating Factors

AE? (6)

A
  • Bone loss: G-CSF increases osteoclast activity, leading to bone resorption.
  • Joint pain: G-CSF appears to stimulate cytokine release, leading to joint pain.
  • Renal dysfunction: G-CSF causes a transient and reversible renal impairment, believed to be caused by leukostasis (clumping of leukocytes) in the kidneys.
  • Acute respiratory distress: G-CSF can lead to lung injury because of accumulation and activation of neutrophils in the lungs.
  • Splenomegaly or splenic rupture: Cases of splenic rupture have been reported with G-CSF. balloon like
  • Sickle cell crises: Sometimes fatal in patients with sickle cell disorders
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22
Q

Hematopoietic Growth Factors: Megakaryocyte

(Thrombopoietic) Growth Factors

A

• Megakaryocyte (Thrombopoietic) Growth Factors
- Oprelvekin (IL-11)
- Thrombopoietin
• Oprelvekin (IL-11) and Thrombopoietin stimulate the growth of megakaryocytic progenitors and increase the number of peripheral platelets. They are used to treat thrombocytopenia following cancer chemotherapy.

  • Eltrombopag (oral) and romiplostim (injectable) are recently approved thrombopoietin agonists.
  • IL-11 treatment is associated with dizziness, headache and fatigue. Recombinant human trombopoietin is supposed to be better tolerated.
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23
Q

what are 2 types of agents that can treat osteoporosis?

A
  1. antiresorptive drugs

2. anabolic agents

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24
Q

how do antiresorptive drugs work?

A

decrease bone loss, e.g. bisphosphonates, calcitonin, selective estrogen receptor modulators (SERMs), denusomab , calcium

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25
Q

how do anabolic agents work?

which has both actions of antiresorptive and anabolic?

A

that increase bone formation, e.g. PTH, teriparatide .

•Strontium has both actions (antiresorptive and anabolic

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26
Q

Bisphosphonates (BPs)

name 2 types and common drugs of each

A

Aminobisphosphonates: (2 phosphates and an amino group)
alendronate, risedronate, pamidronate, zoledronate

Non-Aminobisphosphonates: etidronate,clodronate

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27
Q

Bisphosphonates (BPs)

how do aminobisphosphonates work?

A

Disrupt the mevalonate pathway, a pathway involved in the posttranslational modification of proteins that are involved in cellular signaling.

Disruption of the mevalonate pathway interrupts
osteoclast function and leads to apoptosis of the osteoclast

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28
Q

Bisphosphonates (BPs)

how do non-aminobisphosphonates work?

A

Increase the accumulation of cytotoxic metabolites within osteoclasts, interfering with their function and possibly leading to osteoclast cell death

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29
Q

Bisphosphonates (BPs)

Indications (8)

A

• Osteoporosis
• Paget’s disease of the bone (results in enlarged, deformed bones) - enlarged soft bone w/ less calcium
• Hypercalcemia:
• Malignancy
• Primary hyperparathyroidism (continuous parathyroid
hormone [PTH] release causes bone demineralization)
• Bone metastasis causing osteolysis:
• Multiple myeloma
• Bone metastases of malignant tumors

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30
Q

Bisphosphonates (BPs)

contraindications (2)

A

Hypocalcemia (low calc): BPs have exhibited decreases in serum calcium. It is recommended that deficiencies in calcium be addressed before initiation of therapy.

Poor renal function: BPs are eliminated renally

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31
Q

Bisphosphonates (BPs)

AE (4)

A

• Gastrointestinal: nausea, dyspepsia
• Esophagitis or esophageal erosion
• Osteonecrosis of the jaw with higher doses, jaw easily broken.
• Aminobisphosphonates also cause fever, flulike
symptoms are a transient, typically first-dose phenomenon seen with intravenous administration

32
Q

Estrogens and Related Compounds

common drug name
MOA?

A

Raloxifene

- SERM, selective estrogen receptor modulators. It stimulates osteoblasts and inhibits osteoclasts

33
Q

Estrogens and Related Compounds

Raloxifene
AE (2) + use?

A

Hot flushes, leg cramps, flu-like symptoms and peripheral oedema.
• Thrombophlebitis and thromboembolism.
• Raloxifene is not recommended for primary prevention of osteoporotic fractures, but is one alternative to a bisphosphonate postmenopausal women who cannot tolerate a bisphosphonate

34
Q

Parathyroid Hormone (PTH)

structure?
common drug?

A

Parathyroid hormone, which consists of a single-chain
polypeptide of 84 amino acids

Teriparatide

35
Q

Parathyroid Hormone (PTH)

MOA?
key effects?
receptor?
what does it stimulate?

A

PTH is released from the parathyroid gland. It regulates calcium and phosphate flux across cell membranes in bone and kidney
- Increased serum calcium
- Decreased serum phosphate
- Increased osteoclast activity in bone (indirect by increase RANKL activity
• PTH increases both resorption and formation but the net effect of excess PTH is resorption.

  • actions largely mediated through the PTH-1 receptor. • anabolic effects are mediated by direct effects of PTH on osteoblasts, increasing their number and inhibiting their apoptosis.
  • PTH also stimulates insulin-like growth factor (IGF-1) in osteoblasts, and IGF-1 also has anabolic effects on bone.
36
Q

Parathyroid Hormone (PTH)

contraindications? (6)

A

• Children or young adults with open epiphysis. (where bone is elongated)
• Hypercalcemia: PTH already raises Ca2+ levels.
• Active Paget’s disease of bone.
• Skeletal metastases or skeletal malignant conditions.
• History of radiation to the skeleton: risk of osteosarcoma
• Pregnancy and lactation: deleterious effects on fetal
bone development are possible

37
Q

Parathyroid Hormone (PTH)

AE (4)

A

• Hypercalcemia (mild): PTH increases serum calcium.
• Leg cramps may occur.
• Nausea may occur.
• Orthostatic hypotension: PTH infusions have a
vasodilatory effect in animals

38
Q

Vitamin D Replacement

what are the 2 major forms of vit d replacements?
what does it regulate generally?

common drugs

A

• The two major forms of vitamin D replacements are
vitamin D2 and vitamin D3.
• Vitamin D is an important regulator of calcium and
phosphate homeostasis and bone metabolism. It works
in conjunction with PTH

39
Q

Vitamin D Replacement

common drugs

A

Calcitriol, ergocalciferol (vitamin D2), calcipotriene,

doxercalciferol, paricalcitol

40
Q

Vitamin D Replacement

explain the vitamin d endocrine pathway

A
  • Vit D3 formed by UV in skin goes to liver and gets converted to calcifediol (25(OH)D3)
  • goes to kidney and becomes calcitriol (1,25)
  • calcitriol enters blood and increases differentiation of osteoblasts and plays a role in calc and phos homeostasis
  • calcitriol negative feedback on parathyroid hormone release
41
Q

Vitamin D Replacement

action of drugs on vitamine D endocrine system?

exogenous ergocalciferol (vit D2)
alfacalcidol
exog calcifediol
exog calcitriol

A
  • exogenous ergocalciferol (vit D2): formed in plants by UV is converted to D2 metabolits in liver and kidney (becomes Vit D3 in liver)
  • alfacalcidol, exog calcifediol: increases formation of calcifediol in kidney to calcitriol
  • exog calcitriol: increases blood calcium which negatively acts to inhibit parathyroid hormone release/activity
42
Q

Vitamin D Replacement

dosage forms for calcitriol?
indications (4)

AE? (1 main)

A
  • Calcitriol is available in oral and intravenous formulations. It is a lipid-soluble vitamin and therefore can accumulate and cause toxicity
  • Osteoporosis
  • Hyperparathyroidism
  • Osteomalacia
  • Rickets

Symptoms are primarily induced by hypercalcemia, which include GI pain, renal stones, and psychiatric disturbances.

43
Q

RANKL Inhibitors

common drug? indication?

what is the pathway for triggering osteoclast diff and activation?

A

denosumab for osteoporosis

  • osteoblast is stimulated to express a surface ligand, RANK ligand (RANKL) which reacts witha receptor on osteoclast called RANK (receptor activator of nuclear factor kapa B)
  • this receptor causes diff and activation of osteoclast progenitors
  • hbipohosphonates inhibit bone resorption by osteoclasts
  • anti-RANKL antibodies (denos) bind RANKL and prevent the RANK-RANKL interaction
44
Q

RANKL Inhibitors

MOA?

A

• RANKL (receptor activator of nuclear factor kappa
ligand) is a cytokine member of the TNF superfamily
• The binding of RANKL to RANK results in increased
bone resorption through the differentiation, activation,
and prolonged survival of osteoclasts.
• Denosumab is a new fully humanized monoclonal
antibody that binds RANKL and through binding causes
inhibition of RANKL and thus inhibits osteoclast activity.

45
Q

RANKL Inhibitors

AE 4

A
  • Eczema (small increase in risk)
  • Hypocalcemia
  • Increased risk of infections (ie cellulitis)
  • ONJ and atypical fractures
46
Q

Calcitonin

common drug
MOA?

A

salcatonin (synthetic salmon calcitonin)

  • It decreases the reabsorption of both calcium and
    phosphate in the kidney
  • it inhibits bone resorption by binding to a specific receptor on osteoclasts, inhibiting their action.
47
Q

Calcium Salts

AE?

A

ral calcium salts can cause gastrointestinal disturbance.
• Intravenous administration in emergency treatment of
hyperkalaemia requires care, especially in patients
receiving cardiac glycosides, the toxicity of which is
influenced by extracellular calcium ion concentration

48
Q

name 5 groups of drugs that are antiinflammatory for rheumatoid arthritis

A
  1. Non-steroidal anti-inflammatory drugs (NSAIDs) and
    the coxibs.
  2. Disease-modifying antirheumatic drugs (DMARDs),
    including some immunosuppressants.
  3. The glucocorticoids. (steroidal)
  4. Anticytokines and other biological agents.
  5. Other drugs that do not fit into these groups,
    including antihistamines.
49
Q

synthetic DMARD
methotrexate

MOA?

indication

A

Has marked anti-inflammatory action in rheumatoid disease and cytotoxic in the larger doses used to treat cancer.

MOA
Folate antagonist and thus interferes with thymidylate synthesis (which is essential for DNA synthesis)

Indication
Rheumatoid arthritis; also used in psoriasis, ankylosing spondylitis (inflamm of spine), polymyositis (inflamm of muscle) and vaculitis (inflamm of blood vessel)

50
Q

synthetic DMARD
methotrexate

AE? (3)

dosage form, half-life

A
  • Gastrointestinal disturbances, dose-related liver toxicity.
  • Bone marrow depression and pneumonitis can occur
  • anemia due to bone marrow supp (give folic acid)

Given orally; has active metabolite. Half-life 6–9h

51
Q

synthetic DMARD
sulfasalazine

AE? (4)

dosage form, half-life

A

Nausea & vomiting, headaches, rashes. About a third of patients discontinue the drug because of side effect

Given orally; only ~15% is absorbed in the GIT. Half-life 6–16h.

52
Q

synthetic DMARD
Leflunomide

MOA?

indication (1)

A

Gives rise to a metabolite that inhibits dihydrooratate
dehydrogenase; this results in inhibition of T-cell proliferation and decreased production of autoantibodies by B cells.
- inhibits immunity

indication: RA

53
Q

synthetic DMARD

Targeted synthetic DMARD

for RA (name 2)
for psoriatic arthritis (name 2)
A

– RA: tofacitinib, baricitinib
• They Inhibit Janus Kinase (JAK)

– Psoriatic arthritis (PsA): apremilast, tofacitinib
• Apremilast: The drug acts as a selective inhibitor of
the enzyme phosphodiesterase 4 (PDE4) and
inhibits spontaneous production of TNF-alpha from
human rheumatoid synovial cells.
• Tofacitinib: JAK inhibitor

newly made drugs, for alopecia

54
Q

biologic DMARD

name 2

MOA

A

Biologic - mostly antibodies and against inflamm cytokines like interleukin and TNFa
An anticytokine antirheumatoid drug. Reduces joint inflammation and symptoms of rheumatoid arthritis. Reduces symptoms of Crohn’s disease.

Infliximab

  • Adalimumab is also an anti-TNFalpha antibody (half-life 10– 20 days).
  • Etanercept another anti-TNF-alpha antibody (given
    subcut. twice a week; half-life ~5 days).

It is a monoclonal antibody against TNF- that binds with the TNF-alpha and prevents its interaction with cell surface receptors in inflammatory cells

55
Q

biologic DMARD

infliximab
dosage form, half-life
AE (4)

A

Given by i.v. infusion every 4 weeks. Half-life 9–12 days

Nausea, vomiting, headache, upper respiratory tract
infections with cough

56
Q

Drugs Used in Gout
Colchicine

MOA?

A

Inhibit multiple proinflammatory mechanisms, while enabling increased levels of anti-inflammatory mediators by following mechanisms;

  • inhibits microtubule polymerization by binding to its constitutive protein, tubulin, which is essential to mitosis.
  • inhibits activation and migration of neutrophils to sites of inflammation
  • interferes with the inflammasome complex found in neutrophils and monocytes that mediate interleukin-1β activation, a component of inflammation
  • inhibits superoxide anion production in response to urate crystals
  • interrupts mast cell degranulation
57
Q

Drugs Used in Gout
Colchicine

AE (5)
contra

A

• Colchicine has a narrow therapeutic index. Narrow window of therapetuic and toxic fx, small increase in dose can be toxic
• Gastrointestinal: Diarrhea is virtually a guaranteed side
effect when colchicine is given in doses suitable for acute attacks of gout.
• Bone marrow suppression: Antimitotics preferentially
target rapidly dividing cells, such as those found in the bone marrow.
• Myopathy may occur. (weak muscle)
• Neuropathy may occur

contra • Renal failure: increased risk of toxicity

58
Q

Uricosurics

name prototye and other drug

indication

A

Uricosurics lower uric acid levels in blood as a treatment for gout.

Prototype and Common Drugs
Prototype: Probenecid
Others: Sulfinpyrazone

gout

59
Q

Uricosurics

MOA

A

Uric acid levels in the blood are elevated in gout, and one treatment strategy is to lower uric acid levels by enhancing uric acid excretion. Probenecid is completely reabsorbed by the proximal tubule and prevent uric acid reabsorption.

60
Q

Uricosurics

contra (3)
AE (3)

A

contra
• Renal insufficiency.
• Urolithiasis (renal stones or calculi).
• Peptic ulcer

AE
• Probenecid is well tolerated.
• Gastrointestinal irritation is usually mild.
• Allergic reactions usually are mild and occur in 2% to 4% of patients

61
Q

Uricosurics
Xanthine oxidase inhibitors

name prototye and other drug

indication

A

Prototype and Common Drugs
Prototype: Allopurinol
Others: Febuxostat

decrease uric acid synthesis and
are used in gout

  • Gout
  • Renal stones composed of uric acid
  • Complicated hyperuricemia
62
Q

Uricosurics
Xanthine oxidase inhibitors

MOA

  • allopurinol
  • febuxostat
A
  • Allopurinol is a purine analogue of hypoxanthine and is a substrate for, and inhibitor of, the enzyme xanthine
    oxidase. Xanthine oxidase converts hypoxanthine to
    xanthine to uric acid; inhibition therefore reduces the
    production of uric acid
  • Febuxostat is a new nonpurine inhibitor of xanthine oxidase. A significant difference from allopurinol is that being a nonpurine, it does not inhibit purine or pyrimidine synthesis, while allopurinol does
63
Q

Uricosurics
Xanthine oxidase inhibitors

contra (1)

A

contra: Previous hypersensitivity reactions to allopurinol

64
Q

Uricosurics
Xanthine oxidase inhibitors

AE

  • allopurinol (4)
  • febuxostat (2)
A

Allopurinol
• Skin reactions: Both mild and severe reactions can occur.
• Rarely, toxic epidermal necrolysis or Stevens-Johnson
syndrome occurs, which can be fatal.
• Liver reactions: Severe hepatic reactions including elevations of liver enzymes, fever, eosinophilia, and rash may occur.
• Renal insufficiency.

Febuxostat
• Febuxostat appears to not produce the hypersensitivity reactions that occur with allopurinol.
• Increase in the risk of myocardial infarction, stroke, and cardiovascular death with febuxostat.

65
Q

prox tubule

what is it permeable to?

A
  • Freely permeable to water and solutes.
  • Na+-K+-ATPase in the basolateral membrane provides the Na+- gradients (low cytoplasmic Na+ concentrations) for passive transporters in the apical membranes which facilitate Na+ entry (reabsorption) from the tubular fluid down a concentration gradient.
  • 60–70% of the filtered Na+ and >90% of HCO3- is absorbed in the proximal tubule.

Na+ is passively transported and will be actively transported through basolateral membrane using sodium potassium ATPase channel

Active transport of chloride, bicarbonate, glucose, aa, organic solutes

Most of where reabs happens

66
Q

Loop Diuretics

name 2 drugs

indications? (6)

A

• Furosemide
• Bumetanide
• Most powerful diuretics
- hiogher sodium release and more flow of urine compared to thiazides

Used to treat salt & water overload
associated w/
• Acute pulmonary edema
• Chronic heart failure
• Cirrhosis of the liver
• Nephrotic syndrome
• Renal failure
• Preferred for hypertension with poor renal function
67
Q

Loop Diuretics

MOA?

A

• Inhibit the Na+/K+/2Cl- carrier in the luminal membrane of the thick ascending limb (bind to the Clbinding site)
– The most powerful diuretics
– Cause excretion of 15-25% of filtered Na+, stay in lumen to be excreted

Also have vascular actions
– Vasodilation independent of the diuresis (may involve reduced responsiveness to angiotensin II (or increase in vasodilation prostaglandins) & noradrenaline)

68
Q

Loop Diuretics

AE (4 main)

A
  • Excessive Na+ & water loss (especially in elderly people)
  • *Hypovolemia: Increase of blood pH, bicarbonate pH increases as plasma volume is reduced due to loss of water
  • *Hypokalemia: extra care for heart failure, CBD as toxicity is worse
  • Metabolic Alkalosis
  • Hypomagnesaemia
  • *Hyperuricemia: increase urea, lead to gout
  • Reduced renal perfusion
  • *Hearing loss: due to impaired ion transport in inner ear

uncommon
• Rashes
• Bone marrow depression
• Contraindicated in people with sulfa allergy

69
Q

Thiazides

2 main drugs
compare to loop diuretics

indications? (4)

A
  • Bendroflumethiazide
  • Hydrochlorothiazide
  • Less powerful than loop diuretics
  • Acts synergistically with loop diuretics
  • Related drugs include chlortalidone, indapamide & metolazone
  • Hypertension
  • Mild heart failure
  • Severe resistant edema
  • Nephrogenic diabetes insipidus
  • Preferred for hypertension with normal renal function
70
Q

Thiazides

MOA?

A

• Bind to the Cl- site of the distal tubular Na+/Cl- co-transport system
– Induce natriuresis with loss of Na+ and Cl- ions (stay in lumen)
– Stimulate renin secretion (leads to angiotensin formation & aldosterone secretion)
• Unlike loop diuretics, thiazides reduce Ca2+ excretion
– Potentially advantageous in elderly patients at risk of osteoporosis

71
Q

Thiazides

AE? (3)

A
  • *Erectile dysfunction (less common with low doses and is reversible)
  • Hypochloremic alkalosis
  • *Impaired glucose tolerance
  • Hyponatremia (especially in the elderly)
  • *Hypokalemia
  • Rashes and blood dyscrasias (uncommon)
72
Q

Potassium Sparing Diuretics

name 2

indication (4)

A

main drugs are aldosterone antagonists
• Spironolactone
• Eplerenone

  • Limited action when used singly
  • These drugs prevent hypokalemia when combined with loop diuretics of thiazides
  • Resistant essential hypertension
  • Heart failure
  • Primary hyperaldosteronism
  • Secondary hyperaldosteronism (hepatic cirrhosis)
73
Q

Potassium Sparing Diuretics

MOA?

A

• Compete with aldosterone for its intracellular receptor

– Inhibit distal Na+ retention and K+ secretion

74
Q

Potassium Sparing Diuretics

AE (2)

A
  • *Hyperkalemia: beneficial if you use potassium sparing diuretics to compensate this effect
  • GI upset
  • *Gynecomastia, menstrual disorders & testicular atrophy (less w/ eplerenone)
75
Q

Other Diuretics
Triamterene/Amiloride

when are they used?
MOA?
AE (1)

A
  • Limited action when used singly
  • These drugs prevent hypokalemia when combined with loop diuretics of thiazides
  • Inhibit Na+ reabsorption in the collecting tubules by blocking lumenal Na+ channels regulated by aldosterone
  • *hyperkalemia and GI upset
76
Q 
Other Diuretics
Osmotic Diuretics (Mannitol)

when are they used?
MOA?
AE (1)

A

inhibits reabsorption of water and sodium

  • Mannitol is a 6-carbon sugar alcohol
  • Pharmacologically inert substances that are filtered in the glomerulus but are not reabsorbed
  • Exert their actions on parts of the nephron that are permeable to water (all parts except ascending loop)
  • Are used in acute renal failure
  • Also used for treating acutely raised intracranial or intraocular pressure
  • *Can increase risk for precipitating left ventricular failure
  • Other adverse effects include headache, nausea & vomiting

233 2nd midterm (13 decks)

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