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219 Cards in this Set
- Front
- Back
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a woman has an abrupt onset of blurred vision, hemiparesis, and headache and is found to have a throbmus within a large intrcranial artery. What drugs should she be given?
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Ateleplase
Reteplase Tenecteplase |
|
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what is the mechanism of action of Niacin?
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activates lipoprotein lipase thus increases chylomicron-TG removal from plasma
inhibits lipolysis in adipose tissue thus reduces FFA supply that liver uses for TG synthesis and incorporation into VLDL |
|
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what are the effects of Niacin?
|
lowers LDL and TG
increases HDL |
|
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what are the clinical uses for Niacin?
|
hypercholesterolemia
hypertrigllyceridemia hypercholesterolemia and hypertriglyceridemia Low HDL |
|
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what are the adverse side effects od Niacin?
|
cutaneous flushing
hepatitis increase blood glucose aggravate peptic ulcer myopathy, rhabdomyolysis |
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should fibrates and niacin be used in combination?
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NO
|
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is Colesevelam okay to administer with statin?
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YES
|
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Can a combination of Ezetimibe and a statin be used together?
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YES
|
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Should statins be combined with fibrates or niacin?
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YES, when monotherapy doesn't work
Niacin + lovastatin/simvastatin |
|
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what are the drugs that are used for hypercholesterolemia?
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HMG-CoA reductase inhibitors: statins
Bile acid binding resins Niacin Ezetimibe |
|
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what drugs are used for hypertriglyceridemia and low HDL?
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Fibrates
Niacin |
|
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Which of the following is LEAST likely to occur in a hypercholsterolemic patient receiving Colestripol?
a. increase elimination of bile salts b. decrease plasma cholesterol c. increased Rc-mediated LDL endocytosis d. decreased plasma HDL e. Increased plasma TG |
D. Decrease plasma HDL
BABR such as colestripol and cholestyramine prevent bile acid reabsorption in the gut results in diversion of cholesterol toward new bile acid synthesis increases liver expression of LDL Rc results in decreased LDL in circulation Increase HDL levels Often increase TB so not used in hypertriglyceridemia |
|
|
Treatment of hyperlipidemic patients with niacin results in:
a. increased plasma VLDL b. decreased plasma cholesterol and TG c. Inhibition of HMG-CoA reductase d. increased plasma HDL e. no significant change in circulating cholesterol |
D. increase plasma HDL
Niacin inhibits VLDL production Statins inhibit HMG-CoA reductase Increases HDL levels more than any other available antihyperlipidemic agent |
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A man with a 20 year history of Type I diabetes mellitus has a LDL of 195 mg/dL, HDL of 15 mg/dL, and a TG of 380 mg/dL. The most appropriate drug for treating this patient's lipid abnormalities is:
|
Gemfibrozil or fenofibrate
|
|
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Treatment of hyperlipidemia with gemfibrozil plus lovastain is associated with a high risk of:
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Myopathy
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an adult male presents with elevated plasma VLDL levels and a very high concentration of circulating triacylglcerol. His LDL is within normal range, his HDL levels are low.
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Niacin
|
|
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What are the hematopoetic drug targets?
|
Iron: Ferrous sulfate, Iron dextran
Vitamin B12: cyanocobalamin, hydroxacobalamin Folic acid: oral folate supplements Hematopoetic growth factors: Epoietin, Filgastrim, Sargomostim |
|
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Definition of anemia
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decreased number of RBC
Decreased quantity of hemoglobin |
|
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Aplastic anemia
|
decreased RBC production following a viral infection, toxin, radiation cancer chemotherapy
|
|
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what are causes of anemia?
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Aplastic anemia
Injury, GI bleeding, heavy menstrual cycle in teenagers Hemolytic: autoimmune hemolytic anemia Nutritional deficiencies Malignancy |
|
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what is the CV adaptation to anemia?
|
Tachycardia
increased CO Vasodilation SOB, weakness, irritability, dizziness |
|
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What is Iron responsible for in Erythropoeisis?
|
hemoglobin
|
|
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what is Vitamin B12 responsible for in Erythropoiesis?
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DNA synthesis
|
|
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what is Folic acid responsible for in Erythropoiesis?
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synthesis of pyrimidines and purine bases and amino acids
|
|
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how long does a RBC circulate?
|
120 days
RBCs are made in the bone marrow |
|
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how is iron stored?
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in the oxidized form +3
|
|
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How is iron absorbed?
|
from the intestine
circulation and is then bound to transferrin Iron is sent to tissues to made into hemoglobin, myoglobin, or enzymes or it is stored as ferritin |
|
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Is intake a normal reason why Iron is deficient?
|
NO
except in children, pregnancy, menstruation, female athletes, and surgery & disease |
|
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where is IRon absorbed?
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Duodenum and proximal jejunum
|
|
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how is the elimination of iron regulated?
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Regulated at the level of absorption and storage
|
|
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Iron Deficiency
|
microcytic anemia
|
|
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what is the treatment for iron deficiency?
|
Oral preparation: Ferrous sulfate/gluconate/fumurate
- Vitamin C enhances absorption - food decreases absorption by 40-60% but is necessary to prevent gastric distress IV or IM when not tolerated: Iron dextran |
|
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what is the treatment for Iron toxicity?
|
Acute: typically children > treat with whole bowel irritation and Deferoxamine
|
|
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what is the treatment for hemochromatosis?
|
Chronic Iron Toxicity
Deferoxamine |
|
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what are the inactive forms of Vitamin B12?
|
Cyanocobalamin
Hydroxocobalamin - Intrinsic factor binds B12 to facilitate absorption B12 absorption is dependent on IF |
|
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what are the active forms of Vitamin B12?
|
Deoxyadenosylcobalamin
Methylcobalamin Enzyme cofactor: methyl transfer in folate metabolism |
|
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what are the biochemical reactions involving folic acid and B12?
|
Folate is reduced by folate reductase to tetrahydrofolate: important in the formation of cells
Two active forms of B12 are cofactors for methylation reactions: conversion of methylmalonyl-coA to succinyl-CoA homocysteine to methionine |
|
|
what reactions require folate?
|
Homocysteine accepts CH3 from methylcobalamin > methionine and then cobalamin back to methylcobalamin
|
|
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what converts cobalamin back to methylcobalamin?
|
methyltetrahydrofolate
|
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what is Succinyl-CoA used for?
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amino acid and fatty acid catabolism
|
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If a patient has B12 deficiency what will the signs be?
|
Megaloblastic anemia: accumulation of large RBC precursor cells
accumulation of methylmalonyl-CoA and homocyestine in serum |
|
|
what could be the cause of B12 deficiency?
|
Pernicious anemia: defective secretion of IF: B12 malabsorption
|
|
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what is the treatment for B12 deficiency due to malabsorption?
|
parenteral injections are required
IM daily for 1-2 weeks then 1 monthly/life |
|
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where is folate reabsorbed?
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proximal jejunum
|
|
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where is folate stored?
|
liver
|
|
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how does a person develop a folate deficiency?
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inadequate intake
alcoholics: poor diet, reduced absorption, metabolism & storage |
|
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what are the signs of Folate deficiency?
|
Megaloblastic anemia
accumulation of large RBC precursor cells |
|
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what is folates job in the body ?
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Enzyme cofactor: DNA synthesis, B12-dependent methionine production, purine, pyrimidine, amino acid synthesis
|
|
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what are the folate dependent reactions?
|
Folate reductase: converts folate > tetrahydrofolate
Need tetrahydrofolate so you can generate B12 dependent methionine |
|
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what causes folate deficiency?
|
several drugs cause decrease folate absorption/metabolism
Methotrexate inhibits folate reductase |
|
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what is the treatment for folate deficiency?
|
dietary supplementation
|
|
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what is EPO?
|
glycoprotein, hematopoetic growth factor
produced by the kidneys in response to hypoxia |
|
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what is the function of EPO?
|
binds Rc of RBC progenitors
Stimulates proliferation/differentiation induces release of reticulocytes from bone marrow |
|
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if there is a deficiency in EPO what is causing it?
|
something going on in the marrow or kidney
|
|
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what is the treatment for EPO deficiency?
|
Recombinant human EPO:
Epoetin Darbepoetin (3X longer half life) Iron supplementation to maintain iron stores folate supplementation often needed as well |
|
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what do GC-SF & GM-CSF do?
|
myeloid growth factors: bind Rc on various myeloid progenitors
stimulate proliferation/differentiation stimulate mature neutrophils |
|
|
what are the GC-SF & GM-CSF?
|
Filgastrim: rHug-CSF
Sargramostin: rHug-CSF serum half life 4 hours Pegfilgrastim: 42 hour half life |
|
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what are GC-SF and GM-CSF used in the treatment of?
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neutropenia associated with chemotherapy and bone marrow transplants
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a 20 year old female complains of lethargy and is found to have blood hemoglobin of 10, low MCV, and low MCHC.
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Patient is iron deficient
- Ferrous sulfate |
|
|
a 54 year old female exhibits sever neutropenia following a course of doxorubicin therapy for breast cancer?
|
needs GC-SF:
Filgastrim, Sargramostin, Pegfilgastrim |
|
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A 65 year old with progressive fatigability and anorexia is found to have low blood hemoglobin concentration and elevated serum concentration of methylmalonic acid.
|
Patient is Vitamin B12 deficient
- Cyanocobalamin |
|
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A 64 year old male leaves Boston on a train going 80 mph, with diabetic neuropathy, end stage renal disease, and exhibits peripheral reticulocytopenia and anemia?
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Patient is deficient in EPO:
Epoetin Darbepoetin |
|
|
what are anti-thrombotic agents used for?
|
Venous thromboembolus: acute, long term prophylaxis, surgical prophylaxis, PE
Acute coronary syndrome: unstable angina, NSTEMI/STEMI, percutaneous coronary intervention STroke: thrombotic Atrial fibrillation Artificial heart valve |
|
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what is the normal process of the coagulation cascade?
|
vasospasm
platelet aggregation: adhesion, activation, aggregation coagulation healing Fibrinolysis |
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how do platelets aggregate?
|
fibrinogen binds > cross-links and aggregation there with the platelet > upregulation of receptors
|
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what is cofactor X responsible for in the clotting cascade?
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converts prothrombin to thrombin
|
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what is thrombin responsible for in the clotting cascade?
|
converts fibrinogen to fibrin
|
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What anti-coagulant drug inhibits the synthesis of coagulation factors?
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Warfarin
|
|
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what anti-coagulant inactivates coagulation factors?
|
Indirectly: Heparin and low molecular weight heparin: fondaparinux, enoxaparin
Direct inhibition: Bivalirudin, Lepirudin, Argatroban, Dibigatran, Rivaroxban |
|
|
what are the clinical uses of Warfarin?
|
used for long term treatment:
DVT Atrial fibrillation Artificial heart valve |
|
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what are the new direct thrombin inhibitors that are available that do not need as much monitoring as Warfarin ?
|
Dabigatran
Rivaroxaban safer and more predictable don't require all the monitoring |
|
|
how does Warfarin work?
|
Structure similar to Vitamin K
Blocks Vitamin K reductase > prevents carboxylation of clotting factors (II, VII, IX, X) |
|
|
what are the adverse effects of Warfarin ?
|
Hemorrhage
Fetal abnormalities: fetal warfarin syndrome, chondrodysplasia punctate |
|
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why are there so many drug interactions associated with Warfarin ?
|
Warfarin is metabolized by the liver
inhibition or induction of the CYP450 direct effects on coagulation |
|
|
What drugs increase the PT?
- make it longer to clot with Warfarin |
these drugs inhibit P450 > increase warfarin in serum
1. Cimetidine 2. Aspirin 3. Cephalosporins 4. Heparin 5. Hepatic disease |
|
|
what drugs cause a decreased PT (clot quicker)?
|
these drugs induce the P450 system > decrease warfarin
1. Barbiturates 2. Rifampin 3. Vitamin K |
|
|
Describe the key points associated with Warfarin?
|
Oral administration with delayed onset
Long-term prophylaxis Vitamin K antagonist Inhibits synthesis of factors II, VII, IX, X monitored with prothrombin time not safe in pregnancy |
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what type of drug is Heparin?
|
indirect thrombin inhibitor
|
|
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what are the clinical uses for Heparin?
|
Acute thromboembolic disorders:
Venous thrombosis Peripheral and pulmonary embolism Disseminated intravascular coagulation |
|
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what are the low molecular weight heparins?
|
Enoxaparin
Dalteparin Tinzaparin |
|
|
describe the pharmokinetics of Heparin?
|
NOT absorbed by the GUT
administered as IV infusion or subcutaneous injection |
|
|
what does Heparin act on?
|
binds to antithrombin III
activates antithrombin III AT-III inactivates activated clotting factors > thrombin, Xa > producing immediate anticoagulation |
|
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what does low molecular weight heparin have its affect on?
|
more on the clotting factors IXa and Xa rather than antithrombin III
|
|
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what are the adverse side effects of Heparin therapy?
|
Hemorrhage
Thrombocytopenia Hyperkalemia Osteoporosis from chronic administration |
|
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what are the direct thrombin inhibitors?
|
Bivalarudin
Lepirudin Argatroban Dabigatran Rivaroxaban |
|
|
what is Lepirudin mainly used for?
|
treatment of heparin induced thrombocyotpenia
|
|
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what is Bivalarudin often used for?
|
percutaneous coronary intervention
|
|
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what is the most common side effect of the Direct thrombin inhibitors?
|
BLEEDING
- Bivalirudin, Lepirudin, Argatroban, Dabigatran, Rivaroxaban |
|
|
what are the clinical indications for Dabigatran?
|
prevention of stroke and systemic embolism in atrial fibrillation
Alternative to warfarin |
|
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what is Rivaroxaban clinically used for commonly?
|
inhibits Xa
prophylaxis of DVT alternative to warfarin |
|
|
what anti-platelet drugs inhibit thrombaxane synthesis?
|
Aspirin
NSAIDS |
|
|
what is the mechanism of action of anti-platelet drugs?
|
Block ADP receptors: clopidegrel, pasurgrel, ticagrelor
Block GPIIb/IIa receptor: Abciximab, tirofiban, eptifibitide |
|
|
what are the clinical uses of Aspirin?
|
unstable angina
transient ischemic attacks and stroke prevention ACute MI |
|
|
what is the mechanism of action of Aspirin?
|
inhibits COX-1 mainly
decreases TXA2 synthesis - give patient low dose so that you only inhibit TXA2 and have minimal effect on prostacyclins |
|
|
what are ADP-inhibitors?
|
Clopidogrel (irreversible)
Prasugrel (irreversible) ticagrelor (reversible) |
|
|
what are the clinical uses for ADP- inhibitors?
|
Clopidogrel, Prasugrel, and Ticagrelor are used to:
prevent thrombotic stroke acute coronary syndrome recent MI Stroke |
|
|
when are ADP inhibitors used in therapy?
|
when patient is unresponsive to aspirin or in combination with aspirin
|
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what is a special precaution that should be taken in administering Aspirin and Ticagrelor?
|
avoid maintenance dose of aspirin > 100 mg with Ticagrelor (ADP-inhibitor)
|
|
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what is the mechanism of action of ADP-inhibitors?
|
block ADP receptors > reduce expression of GP receptors > inhibit platelet aggregation
|
|
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what are Platelet GP inhibitors?
|
Abciximab
Tierofiban Eptifibitide |
|
|
what are Platelet GP inhibitors clinically used for?
|
acute coronary syndrome
recent MI, stroke |
|
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what is Abicixmab?
|
Platelet GP inhibitor
mAB to GP receptor that prevents fibrinogen from binding |
|
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what is Tirofiban, eptifibitide?
|
analog sequence within fibrinogen
Platelet GP inhibitor looks like fibrinogen so fibrinogen cannot cross link but the cell thinks that it is cross-linked by fibrinogen |
|
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What are the clinical uses of Fibrinolytic drugs?
|
catalyze the formation of plasmin
clinical uses: acute MI ischemic stroke (thrombotic) pulmonary embolism |
|
|
what are the tissue plasminogen activators? (tpa)
|
Alteplase
Reteplase Tenectaplase - activated clot bound plasminogen |
|
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what is the mechanism of action of tissue plasminogen activators?
|
convert plasminogen to plasmin
|
|
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when are ADP inhibitors used in therapy?
|
when patient is unresponsive to aspirin or in combination with aspirin
|
|
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what is a special precaution that should be taken in administering Aspirin and Ticagrelor?
|
avoid maintenance dose of aspirin > 100 mg with Ticagrelor (ADP-inhibitor)
|
|
|
what is the mechanism of action of ADP-inhibitors?
|
block ADP receptors > reduce expression of GP receptors > inhibit platelet aggregation
|
|
|
what are Platelet GP inhibitors?
|
Abciximab
Tierofiban Eptifibitide |
|
|
what are Platelet GP inhibitors clinically used for?
|
acute coronary syndrome
recent MI, stroke |
|
|
what is Abicixmab?
|
Platelet GP inhibitor
mAB to GP receptor that prevents fibrinogen from binding |
|
|
what is Tirofiban, eptifibitide?
|
analog sequence within fibrinogen
Platelet GP inhibitor looks like fibrinogen so fibrinogen cannot cross link but the cell thinks that it is cross-linked by fibrinogen |
|
|
What are the clinical uses of Fibrinolytic drugs?
|
catalyze the formation of plasmin
clinical uses: acute MI ischemic stroke (thrombotic) pulmonary embolism |
|
|
what are the tissue plasminogen activators? (tpa)
|
Alteplase
Reteplase Tenectaplase - activated clot bound plasminogen |
|
|
what is the mechanism of action of tissue plasminogen activators?
|
convert plasminogen to plasmin
|
|
|
what is LPL?
|
enzyme responsible for storing and clearing the TG from the adipose tissue and the lipase is breaking down the fatty acids to be taken out
|
|
|
what defines hypercholesterolemia?
|
elevated LDL
|
|
|
what defines hypertriglyceridemia?
|
elevated chylomicrons or VLDL
|
|
|
why is low HDL important?
|
increased risk factor for heart disease
|
|
|
Hypertriglyceridemia type II
|
overproduction of VLDL
low LPL activity |
|
|
Chylomicronemia
|
LPL and cofactor deficiency
|
|
|
Combined hyperlipidemia (IIb)
|
including VLDL production and conversion to LDL
|
|
|
dysbetalipoproteinemia (III)
|
lack of apoE3 & 4
|
|
|
Ligand defective apolipoprotein B
|
defect in ligand domains of apoB100
|
|
|
what drugs are used in the therapy of hyperlipidemia?
|
Statins
Niacin Bile acid binding resins Fibrates |
|
|
what do STATINs do?
|
HMG-CoA reductase inhibitors
decrease serum cholesterol and LDL |
|
|
what are some examples of statins?
|
Lovastatin
Simvastatin |
|
|
why does inhibition of HMG-CoA reductase affect cholesterol?
|
decreases hepatic cholesterol synthesis > upregulated hepatic LDL receptors > uptake of LDL cholesterol > decrease serum total and LDL cholesterol
|
|
|
when should a statin be administered?
|
most have short half-lives
- administered in the evening so peak effect occurs during nocturnal peak in cholesterol synthesis |
|
|
what increases the absorption of Lovastatin ?
|
FoOD
|
|
|
what two statins have a long half-life and only need to be administered once be day at anytime?
|
Atorvastatin
Rosuvastatin |
|
|
what statin is not metabolized by CYP3A?
|
Pravastatin
so if you have a patient on many medications this is the best one to prescribe them |
|
|
what drugs can lead to a statin toxicity?
|
CYP3A inhibitors:
Erythromycin Azole antifungal drugs Antidepressants HIV protease inhibitors |
|
|
what are the adverse drug effects of statins?
|
LIVER toxicity
Myositis, myalgia |
|
|
what are the bile acid binding resins?
|
Colestipol
Cholestyramine Colesevelam |
|
|
what is the mechanism of action fo BABR's?
|
bind to bile acids in the GI tract
Prevent reabsorption of cholesterol to replace bile acids Increase LDL receptor expression Decrease LDL Increase TG & HDL |
|
|
what are BABR typically used for?
|
persons not tolerating other drugs
additive effects with other drugs |
|
|
when should Colestipol be administered?
|
Colestipol is a BABR
should be administered before meals and at bedtime NOT absorbed in the gut |
|
|
what are some drug interactions that a BABR could have?
|
inhibit absorption of digoxin, thyroid hormone, and other drugs
|
|
|
what is an inhibitor of intestinal sterol absorption?
|
Ezetimibe
|
|
|
what are the effects of Ezetimibe?
|
decrease LDL cholesterol
decrease TG increase HDL |
|
|
what is the mechanism of Ezetimibe?
|
localizes in brush border of small intestine
inhibits absorption of cholesterol |
|
|
cab Ezetimibe be used in combination with a statin?
|
YES
Vytorin is an example of this: ezetimibe + simvastatin |
|
|
what are the Fibric acid drugs (fibrates)?
|
Gemfibrozil, Fenofibrate
|
|
|
what is the mechanism of action of a Fibric acid?
|
PPAR-alpha-ligand
binds PPAR-aRE > transcription induction > LDL HDL apolipoprotein > increase fatty acid catabolism > decrease VLDL secretion, increase VLDL clearance > decreased TG levels |
|
|
what part of the gene does Gemfibrozil/Fenofibrate affect?
|
PPAR-aRE: promotr region that affects genes that promote TG metabolism
|
|
|
what is the clinical use of Fibrates (Gemfibrozil, fenofibrate)?
|
Treat hypertrigylceridemia
treat low HDL |
|
|
what are the adverse side effects of Gemfibrozil/Fenofibrate?
|
myopathy
Rhabdomyloysis bone marrow suppression exfoliative dermatitis |
|
|
what is the outcome of Niacin treatment?
|
decrease LDL
decrease TG increase HDL |
|
|
what is the mechanism of action of niacin?
|
activated LPL > increases chylomicron/TG removal from plasma
inhibits lipolysis in adipose tissue > decreases FFA supply that the liver uses for TG synthesis & incorporation of VLDL |
|
|
what are the clinical uses of Niacin?
|
Hypercholestrolemia
Hypertriglyceridemia Low HDL |
|
|
what are the adverse side effects of Niacin?
|
cutaneous flushing
hepatitis increase blood glucose aggravate peptic ulcers myopathy, rhabdomyolysis |
|
|
what drugs can be used with a Statin?
|
Colesevelam can be administered with a Statin (BABR)
Exetimibe can be administered with a statin (Sterol absorption inhibitor) |
|
|
what drugs should not be combined together in treatment of hyperlipidemia?
|
avoid fibrates with niacin
|
|
|
can statins be used with fibrates or niacin?
|
Use extreme caution
|
|
|
what drugs are used to treat hypercholesterolemia?
|
HMG-CoA reductase inhibitors (Statins)
Bile acid Binding resins (Colestoprol, Cholestyramine, Colesevelam) Niacin Ezetimibe (inhibitor of sterol absorption) |
|
|
what drugs are used in the treatment of HyperTG and low HDL?
|
Fibrates and Niacin
(Gemofribizol, Fenofibrate) |
|
|
what is the action of Colestipol in the treatment of a patient with hypercholesteroemia?
|
increase elimination of bile salts
decrease plasma cholesterol increase receptor mediated LDL endocytosis increase plasma TG increase plasma HDL |
|
|
why are BABR such as Colestipol and Cholestyramine not used in the treatment of HyperTG?
|
often increase TG in circulation
|
|
|
A man with a 20 year history of type I DM has LDL concentration of 195, HDL 15, TG 380. the most appropriate drug for treating the patient's lipide abnormalities is?
|
Gemfibrozil or Genofibrate
Treatement for low HDL and increased TG |
|
|
the treatment for hyperlipedemia with gemofibrozil plus lovastatin is associated with a high risk of?
|
myopathy
|
|
|
an adult male presents with elevated plasma VLDL levels and a very high concentration of circulating triacylglycerol. His LDL is within normal range but his HDL is low. Treatment?
|
Niacin
decreases LDL decreases TG increases HDL |
|
|
what are prostaglandins?
|
unsaturated fatty acid derivatives with 20 carbon atoms
produces in minute quantities by all tissues act locally on tissues where they are produced rapidly metabolized to inactive products at their site of action do not circulate in significant quantities |
|
|
What is the action of a drug that decreases prostaglandins?
|
Anti-inflammatory: prostaglandins mediate inflammatory events
Analgesic: prostaglandins thought to sensitize neve endings to bradykinin, histamine, and other chemical mediators Antipyretic: prostaglandins increase set point in hyopthalamus, peripheral vasodilation and sweating Antithrombotic: prostaglandins produce TXA2 |
|
|
how does thrombaxane work?
|
product of COX-1 (platelets) increases platelet aggregation
|
|
|
how does prostacylcin work?
|
COX-2 endothelial/inflammatory cells > decreases platelet aggregation
|
|
|
how can aspirin just be anti-thrombotic?
|
low dose-80 mg daily can irreversibly inhibit TXA2 production in platelets without affecting prostaglandin production in the endothelial cell
decrease TXA2 > decrease platelet aggregation > anti-thrombotic effect |
|
|
what are the therapeutic indications for NSAIDS?
|
inflammation: erythema, edema, hyperalgesia
- prostaglandins and other cell mediators - autoimmunity (RA) - infectious agents, ischemia, physical injury Pain: sensitization of pain fibers by prostaglandins Fever: pyrogenic stimulus release of cytokines, increase PG in hypothalamus, increase temp, and decrease heat loss |
|
|
what do NSAIDS inhibit?
|
Cyclooxygenase but not lipooxygenase enzymes
|
|
|
what COX enzymes do NSAIDS inhibit?
|
COX-1 constitutive
COX-2 inducible and associated with inflammation |
|
|
what are the side effects of COX-1 inhibitors?
|
inability to form stomach protecting prostaglandins
|
|
|
what are the pharmacokinetics of Aspirin?
|
absorbed in the stomach and duodenum
low gastric pH keeps most ASA in non-ionized form > enhances absorption |
|
|
describe phase I metabolism of aspirin
|
hydrolyzed to acetic acid and salicylate by esterases in tissues and blood
|
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describe phase II metabolism of aspirin
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conjugation with glycine (liver)
water soluble conjugate excreted in urine Saturation phase II metabolism of aspirin is first order and may shift to zero order kinetics |
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why would aspirin metabolism shift to zero order kinetics with increased dose?
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because of rapid build-up of serum levels of active salicylate (great risk for toxicity)
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when does aspirin reach its peak plasma levels?
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15 minutes
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when does salicylate reach its peak plasma levels?
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2 hours
increases with aspirin dose |
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what is the mechanism of action of aspirin?
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irreversible COX inhibitor
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what is the mechanism of action of Salicylate?
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reversible COX inhibitor
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what are some adverse side effects of Aspirin?
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GI: epigastric distress, nausea, vomiting, microscopic GI bleeding
blood: prolonged bleeding time, NO ASA for one week prior to surgery Respiration: toxic disease > respiratory depression Warning signs: tinnitus |
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what is the treatment for aspirin overdose?
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Gastric lavage
IV sodium bicarbonate: alkalization of urine increases excretion |
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what are the non-specific COX-inhibitors?
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Ibuprofen
naproxen ketoprofen prioxicam indomethacin ketorolac |
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what are the main features of Non-selective COX inhibitors?
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Reversible
Analgesic Anti-inflammatory Antipyretic |
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what non-selective cox inhibitor has the longest half life?
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Piroxicam: 57 hours
Naproxen: 14 hours compared to Aspirin: half life= 3 hours |
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what is the name of a COX-2 selective inhibitor?
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Celecoxib (Celebrex)
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what are the pharmacokinetics of Celecoxib?
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Selective COX-2 inhibitor
easily absorbed: peaks in 3 hours Metabolized in the liver by P450 Excreted in feces and urine Once daily dosage |
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what are the adverse side effects of Celecoxib?
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abdominal pain
dyspepsia diarrhea GI ulcers double that of placebo Kidney toxicity P450 interactions likely |
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what makes acetominophen different from the other COX inhibitors?
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inhibits COX-3 in the CNS
NOT anti-INFLAMMATORY antipyretic and analgesic |
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why does Acetominophen have little effect on the periphery?
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inhibited by peroxides in inflammation site
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what makes Acetominophen dangerous for toxicity?
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Running out of glutathione is the problem
- majority metabolized by conjugation with sulfate & glucuronide minor pathway involves oxidation of acetaminophen by P450 enzymes > potentially toxic intermediate |
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how does the theraputic dose of acetaminophen work?
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quinine intermediate conjugation with glutathione and excreted in urine
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what would a toxic dose of acetaminophen cause?
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Glutathione stores are depleted > quinone intermediate attacks hepatic cell macromolecules > hepatic necrosis
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what is the treatment for acetaminophen overdose?
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Acetylcysteine treats acetaminophen overdose
- protects the liver by maintaining or restoring glutathione levels or acts as alternative substrate for conjugation with and detoxification of reactive metabolite |
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what is Rheumatoid arthritis?
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typically strikes joint causing pain, swelling, and deformity
as synovial membrane becomes inflamed and thickens, fluid build up and joint degrades Synovial membrane usually protects and lubricates joints |
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what is osteoarthritis?
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most common form of arthritis
wearing away of cartilage that caps the bones in your joints |
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what is the mechanism of action of methotrexate in the treatment of RA?
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immunosuppressant
inhibits AICAR transformylase and thymidylate synthase |
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what is the mechanism of action of Chlorambucil and Cyclophosphamide in the treatment of RA?
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cross link DNA
inhibit cell replication |
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what is the mechanism of action fo cyclosporine in the treatment of RA?
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inhibits IL-1/IL-2 receptor production
disrupts T-cell mediated responses |
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what are the TNF-a blocking agents for treatment of RA?
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Adalimumab and infliximab
Etanercept Leflunomide Anakinra |
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what is the mechanism of action of Adalimumab and infliximab in the treatment of RA?
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anti-TNF-a mAB
inhibits macrophages and T-cell function |
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what is the mechanism of action of Etanercept in treatment of RA?
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recombinant fusion protein
TNF-a receptor IgG which binds TNF-a |
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what ist the mechanism of action of Leflunomide in the treatment of RA?
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inhibits ribonucleotide synthesis
inhibits T-cell proliferation metabolite of drug inhibits dihydroorotate dehydrogenase: important in pyramidine synthesis |
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what is the mechanism of action of anakinra in the treatment of RA?
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recombinant form of IL-Ra
IL-1 receptor antagonist is one of the molecules the body synthesizes anyway; want it to have a stronger effect so there will be no inflammation |
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what is GOUT?
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metabolic disorder with high levels of serum uric acid
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what are the risk factors for GOUT?
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primary inherited abnormality in uric acid metabolism
Obesity, high alcohol intake, high BP, abnormal kidney function, drugs |
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what is a key enzyme in the production of uric acid?
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Xanthine oxidase
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what is the function of Allopurinol in the treatment of GOUT?
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inhibits Xanthine oxidase
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what is the function of Probenecid in the treatment of GOUT?
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blocks tubular reabsorption to force it out into urine
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what is Colchicine? how is it used to treat GOUT?
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plant alkaloid used for acute attacks
blocks it downstream to alter immune system prevents polymerization of tubulin into microtubules inhibit LT migration to affected areas inhibit synthesis and release of LT |
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describe how Probenecide, Sulfinpyrazone are used in the treatment of GOUT?
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mechanism of action: increase excretion of uric acid by inhibiting reabsorption of uric acid in the proximal tubule
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How does allopurinol work in treating GOUT?
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inhibits xanthine oxidase
reduces production fo uric acid because it is a purine analog Metabolized to alloxantine which retains capacity to inhibit XO |
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Febuxostat
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New xanthine oxidase drug
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are NSAIDS use in the treatment of GOUT?
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YES
due to toxicity of colchicine, non-salicylate NSAIDS are usually given first in acute attack use: Ibuprofen, Naproxen, Ketoprofen |
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can you Aspirin when treating GOUT?
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NO: competes with uric acid for excretion
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a 67 year old female was diagnosed with RA two years ago. Initially she was prescribed an OTC NSAID. When she no longer responded to NSAID, she was put on a disease modifying anti-rheumatic drug, methotrexate. As her conditioned progressed her therapy was altered and she was given a drug that must be give SC and renders TNF-a inactive. In this 3rd course of action which of the following drugs was the patient given?
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Adalimumab: anti-TNF-a mAB: inhibits macrophages and T-cell function
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a 35 year old male with peptic ulcers often experiences muscle pain associated with his anaerobic exercise routine and his occupation is a construction worker. His father and uncle died of an MI. Which drug is indicated for pain management in this individual
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Acetaminophen
only concerned with muscle pain and not inflammation cannot give non-specific COX- inhibitor since it would aggravate his ulcers due to family history of MI, do not give COX-2 inhibitors because they promote clot formation |
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A 7 yo. boy presents with fever and complains of aching muscles. Ear and throat exam do not indicate a bacterial infection. The physician suspects a viral etiology. What is the appropriate treatment of this child's symptoms?
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Acetaminophen
only concerned with fever |
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a young female just finished playing soccer game in which she twisted her ankle. In addition to pain and swelling in her ankle, she soon began to develop a headache. After one hour, the ankle swelling decreased in response to an ice pack, but she still had a headache and a fever. Her parents gave her 500 mg of acetaminophen which reduced the pain and her fever but didn't affect the inflammation in her ankle. Why was acetaminophen ineffective?
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It only acts within the CNS, it does not have any peripheral effects
It is only antipyretic and analgesic |
