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116 Cards in this Set
- Front
- Back
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beta blockers
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- propranolol (non selective)
- atanolol - cardioselective - nadolol - long acting - these block renin production |
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alpha adrenergic sympatholytic receptor antagonist
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prazosin and terazosin
- block symp. contractin of arterial smooth muscles - vasodialtors - decrease TPR |
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indirect acting sympatholytic drugs
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- alpha 2 agonist - clinidine - reduces sns activity.
- catecholamine release inhibitors (reserpine) - inhibits release of catecholamine receptors. |
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vasodilators
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- relax vascular smooth muscle.
two types - sympatholytic drugs - block sympathetic ns induced contraction of arterial smooth muscle. - direct vasodilators - directly dilate arterial smooth muscle - oral drugs - used for outpatient tx of hypertension - hydralazine - |
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oral direct vasodilator drugs
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- hydralazine - selective arterial blocker
- CCB - block voltage dependent calcium channels on vascular smooth muscles - minoxidil - highly effective with lots of side effects |
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direct vasodilators continued
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- parenteral drugs
- used for emergency room situations - sodium nitroprusside - vasodilator - diazoxide - highly effective and long acting = not a first choice drug. |
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vasodilator drugs mech. of action
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- NO - causes hyperpolarization and release of K+ which blocks calcium channels (this stops the binding of calcium to the sarcoplasimic reticulum) which would then bind to troponin c and cause smooth muscle contraction
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vasodilator mech. of action cont.
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- CCBs block ca channels directly
- alpha one antagonists block a g protein that activates calcium channels. - hydralazine, minoxidil and diazoxide all cause hyperpolarization which blocks the ca channels and this stops the whole contraction process. |
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CCB's mech. of action
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block L type voltage dependent calcium channels on cardiac and or vascular smooth muscle.
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types of ccb's
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- cardioactive smooth muscles - relax vascular smooth musche and reduce cardiac output (decrease heart rate, AV conduction and force of contraction
- verapamil - diltiazem NON cardioactive CCB's - relax vascular smooth muscle but have little effect on cardiac output. - dihydropyridines (all end in dipine) - short acting dihydropyridines, CCB's = increased risk of MI relative to patient taking diuretics or beta blockers. - use long acting drugs or extended release formulations of short acting ccb's |
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vasodilator side effects
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- all/ most
- postural hypotension - flushing, sweating - headache reflex responses - reflex tachycardia - rational for co administration with beta blockers - reflex fluid retention - rationale for co admin. of diuretics - Vasodilators are almost always prescribed with a diuretic or beta blocker to prevent reflex responses. |
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bVconsequences of feedback regulation = indirect effects of vasodilators
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- vasodilator administration --> relaxation of smooth muscle --> decrease in tpr --> reduced bp --> detection by baroreceptors --> increased sns activity and a decrease in PNS activity --> reflex increase in heart rate.
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beta blockers that are also vasodilators will help prevent this feedback loupe.
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- decrease CO and TPR
- beta blocker/ vasodilators - carvedilol - mixed beta 1 and alpha 1 antagonist - nebivolol - beta blocker that promotes NO production |
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consequences of feedback regulation - indirect effects of vasodilators
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- vasodilator administration --> relax--> decrease in TPR --> reduced bp--> detection by juxtaglomerular cells in kidney--> increased renin and at 2 production --> reflex increase in sodium reabsorption = increase blood volume and edema.
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angiotensin related agents
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- block effects of the renin at system, thereby reducing bp primarily by inhibiting at 2 induced
- vasoconstriction - increases in aldosterone production |
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angiotensin related agents
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ace inhibitors
angiotensin receptor blockers (arb's) Renin inhibitors |
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renin inhibitors
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- block renin which cleaves angiotensinogen to angiotensin 1
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ace inhibitors
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block conversion of at 1 to at 2 by blocking ace activity
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angiotensin receptor antagonists
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- blocks binding of at2 to AT1 receptors (this normally would cause direct vasoconstriction, aldosterone synthesis in adrenal cortex and vasopressin release)
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ace inhibitors
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- all end in suffix -Pril
- captopril - no met. needed, ass. with higher risk for side effects. - enalapril - pro drug metabolized into active ace inhibitor. side effects - dry cough (bradykinin effect due to ACE inhibition) - angioedema (rapid non allergic swelling of skin and mucosa; also due to bradykinin) - hyperkalemia - reduced sodium pottasium exchange in kidney because it stops aldosterone production. - reduced kidney function - - teratogenic - DO NOT USE IN PREGNANCY. |
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angiotensin receptor blockers (ARB's)
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- competitive antagonists at AT1 receptors
- SELECTIVE - no effects on metabolism of bradykinin and other biologically active substances - less side effects - produce hyperkalemia - Complete blockade of AT1 mediated angiotensin 2 side effects with less at2 receptor antagonism. - Losartan and Valsartan (all end in artan) |
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renin inhibitors
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- inhibit renin conversion of at to at1 and reduce at2 levels therefore.
- rationale - ACE inhibitors and ARB's produce compensatory increases in renin synthesis and activity. |
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hemostasis (spontaneous rest of bleeding from damaged vessels)
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- initial response (vasospasm)
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clotting factor cascade
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- clotting factors are proteases
- proteolytic digestion of these clotting factors results in thier activation - activation occurs as a cascade with the first activated factor digesting and activating the next - the end result of includes the production of thrombin and fibrin and the formation of a clot. |
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anticoagulation
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- protease inhibitors - antithrombin 3 blocks the protease cascade from occuring
- tissue plasminogen activator - fibrinolytic pathway that promotes the conversion of plasminogen to plasmin which then eats up the clots. |
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types of blood clots
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- all clots have fibrin and platelets involved
- white thrombus - forms in high pressure arteries and involves platelets forming in the damaged endothelium and aggregation with little binding with fibrin - pathology - local ischemia due to arterial infarction - in coronary arteries ; MI and AP Red Thrombus - forms in low pressure veins and in the heart; result of platelet binding and a lot of fibrin forming a long tail in which RBC's get enmeshed. - pathology - emboli and distal pathology - DVT resulting in pulmonary emboli, cardiogenic emboli resulting in embolic stroke. - emboli - traveling clot. |
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anti clotting agents
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- anti coagulants - regulate the function and synthesis of clotting factors
- primarily used to prevent clots from forming in the venous system and heart |
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antithrombotics/ antiplatelets -
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- inhibit platelet function
- primarily used to prevent clots from forming in the arteries (white thrombi) |
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thrombolytics/ fibrinolytics
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- destroy blood clots aftery they form
- re establish blood flow through vessels once clots have formed. |
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anticoagulants
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- inhibit the synthesis and activity of clotting factors
- used to treat disorders secondary to RED thrombi and reduce the risk of emboli - protect against embolic stroke, pulmonary emboli - administer to pt. with dvt, atrial arrhythmias and other conditions that predispose towards red thrombi. - side effects; excessive bleeding - parenteral anti - coagulants - Heparins - indirectly inhibit thrombin via anti thrombin 3 - parenteral direct thrombin inhibitors - peptide analogs of hirudin, purified from leeches and directly inhibit thrombin... lepirudin - (used in patients who can't take heparin) - oral anticoagulants - warfarin |
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heparins
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parenteral anticoagulants
- binds to and stimulates antithrombin 3 - an endogenous inhibitor of clotting factor. - molecular weight determines activity - unfractionated heparin - combo of low and high has more activity - low MW- less activity (enoxaparin) - polysacharides - very hydrophilic and susceptible to digestion, must be given via iv or SC - common uses - prevention of emboli during surgery or in hospitalized patients - heparin locks - prevent clots from forming in catheters - side effects - bleeding, heparin induced thrombocytopenia - immune response resulting in increased clotting. |
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warfarin
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- oral anti coagulant
- prevents vitamin k re activation by inhibiting vt k epoxid reductase - active vit. k is required for synthesis of clotting factors in both the extrinsic and intrinsic pathway. - side effects bleeding, osteoporosis, transient risk for necrosis of extremities due to paradoxical clotting. - teratogenic - avoid during pregnancy. - common uses are outpatient tx. of deep vein thrombosis, cardiac conditions that generate emboli. |
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genetic variation of genes that effect warfarin metabolism
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- variation in cyp2c9 reduces warfarin metabolism - increased bleeding risk.
- Vkorc 1 subunit reduces warfarin sensitivity. - increased clotting risk. |
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fibrinolytics
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- destroy blood clots after they form.
- function like TPA |
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fibrinolytic drugs
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- tpa drugs
- alteplase - recombinant - streptokinase - purified from bacteria clinical uses - embolic/ thrombotic stroke - acute MI - pulmonary emboli - clear occluded iv catheters. |
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tpa and the tx of stroke
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- leading cause of adult disability, 3rd leading cause of stroke
80% result from occlusion of cerebral arteries - embolic stroke - emboli from red thrombi (typically cardiogenic) - thrombotic stroke - occlusion resulting from white thrombi (atherosclerosis related) - 20% result from bursting of blood vessels - hemmhoragic stroke |
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tpa tx. and activity
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- most effective within 3 hours after embolic stroke, also effective vs. thrombotic stroke
- can worsen damage produced by hemmhorragic stroke. |
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anti thrombotics (anti platelet drugs)
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- inhibit platelet funciton by interfering with synthesis and release of chemicals from activated platelets including
- thromboxane A2 - a prostaglandin derived from arachadonic acid via the cox pathway that is released from platelets and promotes aggregation and local vasoconstriction. ADP - adenosine diphosphate - nucleotide released from activated platelets. binds to purinergic receptors on other platelets resulting in aggregation. - used to prevent heart attacks/ acute mi, arterial thrombosis of the limbs resulting in intermittent claudication, thrombotic/ ischemic stroke, and percutaneous coronary interventions. |
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aspirin
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- COX inhibitor - decreased TXA2 production
- uses - analgesia - headache, othe aches - non steroidal anti inflamm. drug - reduces fefer - all of these are 325 mg. - anti platelet - typically lower doses - 81 mg. - irreversible inhibition (acetylates cox - side effects - gi ulcers, bleeding, tinnitus (ringing of the ear) allergic reactions, reyes syndrome - avoid in kids with viral symptoms |
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adp receptor blockers
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- prevent adp from binding to platelet purinergic receptors
- clopidogrel (plavix) - prodrug metabolized by cyp2c19 to active form - up to 14% of patients have increased amount of this, poor activators - lots of drug interactions - prasugrel - (effient) - also a prodrug - also a prodrug but metabolized by different cyp enzymes with more consistent effects. |
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platelet receptor antagonists
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- antagonize receptors on platelet cell membranes to prevent physical interaction of platelets with fibrinogen and therefore platelet aggregation.
- administered paretnerally for Percutaneous coronary interventionsto prevent reoclusion of coronary vessel - abciximab - anti GP 2b/3 a antibody - tirofiban (aggrastat) - GP2b/3a antagonist use restricted to PCI (angioplasty) |
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use of anti platelet drugs for the prevention of acute mi
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they prevent occlusion or reocclusion due to clot formation.
- protect against heart attack in individulas with coronary heart disease. - when taken at the time and subsequent to a heart attack, aspirin increases survival and reduces the risk of another heart attack. - also protects against thrombotic stroke. |
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prophylactic use of aspirin
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- why - prevents acute mi, also thrombotic stroke and peripheral arterial occlusion
who - moderate to high risk individuals. except for people with a bleeding risk. people with a history of acute mi should be taking aspirin or other anti platelet drugs - concerns - risk for bleeding outweighs benefits in some populations - 75-81 mg is sufficient daily max. dose is 325 mg at the moment of a heart attack taking and chewing 4 baby aspirins is recommended. |
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aspirin vs. adp receptor blocker
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- aspirn - cheaper and works but has the bleeding risk
clopidogrel (adp blocker) - expensive and slightly more effective but it reduces teh risk for GI bleeding with a higher risk for skin rash combination therapy of aspirin, clopidogrel and GP2b/3a inhibitors produce additive effects - combinations are more effective than monotherapy - also more dangerous. |
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termination of anti platelet drug therapy
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- has been shown to produce rebound effects and increase heart attack risk.
- do NOT discontinue the use of aspirin or adp blockers before routine procedures - in cases of more invasive procedure, bleeding risk should be assessed |
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cox inhibitors vs. selective cox 2 inhibitors and coronary heart disease.
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cox 1 produces both TA2 and prostaglandin which leads to platelet activation, promotes clotting and vasoconstriction
- cox 2 pathway only produces platelet inactivation, limits clotting and causes vasodilation. |
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so when you limit only the cox 2 pathway
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- you are increasing platelet activation, pro thrombotic effects and increased risk for CHD.
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patients on anti coagulants -
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side effects include increased bleeding - so they have developed clotting time tests.
- aptt (activated partial thromboplastin time) - for heparin -selectively stimulates teh intrinsic system - pt - for warfarin - index of activity of both the intrinsic and extrinsic activity, internalized normalized ratio greater than 3-4 is a bleeding risk. - may have to prolong procedure or use pro coagulants - anti fibrinolytics - prevent plasmin formation - promote clotting - hemostatic aids - promote natureal hemostatic process - vitamin k - reverses effects of warfarin - protamin E - reverses effects of heparin. |
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angina pectoris; pain in the chest
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- cause - oxygen demands of myocardium exceeds oxygen supply
- pathology - partial obstruction of blood supply to the myocardium via the coronary arteries - symptoms - pain radiating from teh chest area into the chest aria into the jaw bone, back and left arm with intense anxiety |
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types of AP
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- classic - occlusion resulting from formation of atherosclerotic plaques - most common form of AP
- symptoms occur during exercise and stress - high cholesterol is #1 risk factor. - variant angina - spontaneous vasoconstriction of coronary arteries - genetic in origin - symptoms occur at rest |
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classic angina is the result of atherosclerotic plaque formation in the coronary areteries
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- drugs that prevent coronary heart disease/ angina prevent the formation of atherosclerotic plaques.
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atherosclerosis
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- LDL penetrates arterial walls and accumulates in sm. muscle cells in the form of cholesterol esters
- the sm. muscle cells along with activated macrophages are transfomed into lipid filled foam cells. - these foam cells sheer off withconstant blood flow and pull off parts of the vessel walls long with them, exposing underlying tissue. - this facilitates even more lipid entry and induces clotting responses. - the ned result is a plaque with a center consisting of cholesterol deposits and cell components and a cap consisting of aggregated platelets and fibrin. |
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pharmacological prevention of coronary heart disease
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- athersclerotic plaque components - cholesterol from LDL
- white thrombi (platelets) - drugs used to prevent atherosclerosis in coronary arteries - cholesterol reducing drugs - anti platelet drugs (initiate once unstable angine emerges) |
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cholesterol
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- high cholesterol is the #1 risk factor for coronary heart disease which is the #1 killer of americans
borderline levels are >200 mg/dl |
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when cholesterol levels are too high
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- individuals with cholesterol over 240 mg/dl have 2 X the risk of suffering a heart attack or stroke compared wot people with <200 mg/dl
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cholesterol is needed for normal physiology
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needed for normal physiology
- cell membranes and steroids - too much is bad - lipoproteins - spherical particles - carry cholesterol - multiple types of cholesterol defined - LDL - bad - VLDL - bad - HDL - good |
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normal lipid metabolism
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- most of our lipids are obtained by various animal products
- chylomicrons transport cholesterol and triglycerides from teh gut into the general circulation 2. the enzyme lipoprotein lipase in blood vessels cleaves triglycerides from chylomicrons releaseing free fatty acids for storage in adipose tissue or use as an energy source, leaving cholesterol remnants which are taken up in the liver 3. the liver also synthesizes triglycerides and packages them into VLDL along with cholesterol fro release into circulation. 4. lipoprotein lipase - also breaks down VLDL, again releasing triglycerides, to produce IDL which is either rapidly either taken up into the liver or converted to LDL |
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normal lipid met. part 2
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- LDL is the major cholestorol carrier in the blood and is stable for 24 hours.
- LDL delivers cholesterol to cells by binding to an LDL recepot on cells which is internalized resulting in cholesterol uptake. inthe liver cholesterol binds to the LDL recepot and enters cells is excreted in the bile. - hepatic and extrahepatic cells themselves also synthesize cholesterol using the enzyme HMG CoA reductase - LDL receptors expression is regulated accroding to cellular cholesterol levels - elevated - reduced LDL recepotr expression and less removal of LDL from circulation - reduced cellular levles - increased LDL receptor expression and mreo removal of LDL from the circulation. - HDL is also synthesized in the liver. HDL stimulates lipoprotein lipase and acquires cholesterol from the other lipoproteins and from arteries and other sites and returns it to the liver where it can be excreted in the bile. |
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hyperlipidemias
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- hypertriglyceridemia - increased VLDL - some risk for coronary heart disease and pancreatitis
- hypercholesterolemia - increased LDL |
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hyperlipidemia's continued
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- primary - genetically determined and often the result of hyperlipoproteinemias
- ex. hypercholesterolemia - secondary - secondary to other conditions, such as diabetes, hypothyroidism, increased estrogen - multifactorial - the MOST COMMON form of hyperlipidemia - genetic , lifestyle and diet |
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tx. of hyperlipidemia
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- two basid strategies -
1. decrease the amount of lipid entering the blood - low fat or low calorie diets- first line of defense - drugs that reduce lipoprotein synthesis - drugs that reduce dietary cholesterol absorption 2. improve the clearance of lipid from the blood - for VLDL this involves the enzyme lipoprotein lipase - for LDL this involves LDL receptors, the less LDL in the liver the more LDL receptors that iwll be synthesized - more LDL receptors = more efficient removal of LDL from teh blood. |
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drugs used for treating hyperlipidemia
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- hypertriglyceridemia
- niacin - fibric acid derivatives - hypercholesterolemia - bile acid sequestrants - statins - ezetemibe - niacin - combination therapy |
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drugs used to treat hyperlipidemia ; trigylcerides
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- VLDL - primary carrier of triglycerides
- tx of hypertriglyceridemia requires reducing circulating VLDL levels - required to reduce risk for pancratitis |
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drugs that decrease VLDL levels
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- niacin - also most effective at increaseing HDL levels and moderately decreases LDL levels
- fibric acid derivatives (gemfibrozil) - most effective at reducing VLDL but minimal effects on LDL and HDL, used only for hypertriglyceridemia. |
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drugs used to decrease hyperlipidemia ; cholesterol
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- bile acid sequestrants
- reduce LDL and increase HDL - formulations of large non absobable molecules taken orally that bind to bile acids in teh intestine and prevent bile acid re absorption - cholesterol is required for bile acid synthesis in the liver - reduced bile acid conc. means more cholesterol is needed in the liver to make bile which means less circulating cholesterol levels which means there has been an uptick in LDL receptor synthesis. Colesevelam - is best tolerated. |
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drugs used to treat hyperlipidemia ; cholesterol
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- Statin drugs - HMG CoA reductase inhibitors
- atorvastatin (lipitor) - - HMG Coa reductase is a key liver enzyme for the synthesis of cholesterol - by reducing cholesterol synthesis in the liver, cellular concentrations are reduced and LDL recepotrs are up regulated. resulgint in increased removal of LDL from teh blood. - reduces cardiac events by up to 60% and strokes by up to 17% - also produce modest increases in HDL and decreases VLDL |
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organinc nitrates action
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- dilate veins - reduce return of blood to the hear = decreased preload and oxygen demand.
- dilate larger arterioles - increase oxygen supply. |
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use of organic nitrates
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- used for both classic and variant angioa pectoris.
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import. organic nitrate drugs
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- nitroglycerine and iso sorbide di ad mono nitrate
- nitroglycerine is inactivated through first pass met. and therefore are usually givein sublingually as a table or spare or trandermally. - isosorbide di/ mono nitrate - can be administered orally. |
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compensatory responses to nitrate drugs
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- reflex tachycardia = increased o2 consumption
- may require combo therapy with a beta blocker. |
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toxic effects of nitrate drugs
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- headache
- flushing and sweating - hypotension - potentiated by drugs such as sildenafilused to treat ed |
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calcium
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- mediates sm. muscle contraction; enters cells via L type voltage dependent ca channels in vasc. smooth muscle and cardiac muscle.
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CCB non cardioactive
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- amlodipene and nifedipeine
- block channels in vasc. smoth muscle without large effects on cardiac muscles. - vasodilators |
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CCB cardioactive
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- block channels in vas. sm. mscle and in the heart
- vasodialtors and cardiac inhibitors. |
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potentially beneficial effects of ccb's
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- coronary arteries are more sensitive to CCB;s than smaller arterioles.
- increased oxygen delivery via coronary arteries - reduced tpr - little effect son veins. - cardiac suppression - decreased oxygen demand |
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not on cardioactive ccb's
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- dilate coronary arteries and reduce cardiac output.
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ccb's and coronary heart disease
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- monotherapy may be used
- in combination with a beta blocker - non cardioactive dihycropyridene (amlodipine or sustained release nifedipine) |
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first choice for
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prinz mentals angina (variant)
- typically cardioactive. |
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when not to use CCB's
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- unstable ap or patients with acute MI history
- because they are less protective and may prolong healing and may increase risk for recurrent heart attack. |
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use of antiplatelet drugs for the preventionof acute MI
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- prevents the final step of coronary occlusion (clotting)
- aspirin - 75-81 mg. one bby aspirin /day is good enough to sufficient to pretect against people in moderate to high risk who hav no history of MI - at time of heart attack 4 baby aspirn to pretect against reocclusion. - maintain on higher dose 325 mg. aspirin after acute MI to pretect against another heart attack. - ADP blockers - (clopidogrel, and prasugrel) - higher risk indivi. post MI; post PCI surgery. - glycoprotein 2a/3b blockers (abciximab, tirofiban) - during pci surgery. |
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use of clot buster drugs for the tx of acute MI
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- analogs of TPA (alteplase or tpa)
- break down fibrin components of clot to open vessels after coronary occlusion has alreade occured |
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effectiveness of clot busters
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- 50% vs. 90% with angioplasty
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surgical correction of CHD
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- balloon angioplasty
- coronary stents - coronary bypass - drug eluting coronary stents |
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drug eluting coronary stents
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- currently approved
- immunosuppresant/ mitotic inhibitor coated stent are approved to prevent macrophage actions and cell proliferation resulting in stenosis - also prevent healing resulting in increased clottting risk and have been reported to be ass. with increased risk for acute MI; requires use of high efficacy antiplatelet drugs. |
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tumor growth
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- tumor initiation - a genetic mutation leads to abnormal proliferation of a single cell
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tumor progression
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- additional mutations occur within cells.
- advantageous mutations are selected. - selection leads to rapid growing an increasingly malignant tumor cells. antineoplastic drugs - target rapidly dividing cells. |
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phases of the cell cycle
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- G1 phase - prep for dna replication
- s phase - dna replication - G2 phase - prep for mitosis - mitosis - seperation of daughter chromosomes and cell division G0 phase - resting phase. |
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DNA damage checkpoints (s checkpoint)
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detect dna damage before the cell enters S phase (a G1 checkpoint)
- spindle checkpoint - (M checkpoint) - detect any failure of spindle fibers to form properly |
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cancer chemotherapy
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- cytotoxic drugs
- hormonal agents - inhibitors of tyrosine kinase - inhibitors of angiogenesis - cytokines - vaccines |
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log kill hypothesis
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- chemotherapy - 1st order kinetics 9constant % killed)
- 10 to the 12th cells 99.99% is killed bythe drug but 10^8 is left - potential outcomes - untreated cancer - curative local treatment - fraction of cells killed during chemotherapy exceeds rebound in between sessions - resistanc eor drug tolerance results in increased growth between sessions relative to fraction destroye during tx. |
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antineoplastic agents
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- induce apoptosis
- target cells in cell cycle - DNA damage - alkylating agents - antitumor antibiotics - inhibitors of DNA synthesis - antimetabolites - folate synthesis inhibitors - topoisomerase inhibitors - inhibitors of microtubule function - vinca alkaloids - biological modifiers |
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phase specific drugs
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- most active at a particular phase of the cell cycle
- S phase - interfere with dna synthesis - M phase - block the formation of the mitotic spindle. - time dependent - phase specific drugs more effective against tumors exhibiting log growth pattern. |
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phase non specific drugs
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- exert toxic effects on cells in cell cycles, but not selective for a particular phase, note, they are not active in G0 phase
- often bind to and damage DNA, are effectiv in both low growth fraction solid tumors and high growth fraction tumors. - conc. dependent. |
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DNA damaging agents; phase non specific drugs
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- alkylating agents - covalently couple alkyl groups to nucleophilic sites on DNA.
- antitumor antibiotics - cause free radical induced damage to DNA - note; damaged DNA results in apoptosis. |
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alkylating agents
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- mech. of action
- react with dna, rna, proteins resulting in covalent linkages witha variety of groups. - alkylation of DNA results in apoptosis when the cell attempts to divide ( provided DNA repair does not occur) - phase non specific drugs, although peak activity occurs in cells in the late G1 and S phases - alkylating agents are mutagenic (carcinogenic) |
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alkylating agents (mechlorethamine)
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- alkylated guanine
- crosslink DNA - ring cleavage - abnormal base pairing - guanine excision from DNA |
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antibiotics
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- anthracyclines
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antimetabolites
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- purine antagonist or pyrimidine antagonists
- mech. of action - purine or pyrimidine anologues; insertion of DNA - DNA chain termination - DNA strand breakage - inhibition of cell growth |
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folate analogues
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- methotrexate
- conversion of folate to tetrahydrofolate necessary in cells rapidly dividing in order to replicate DNA. - mech. of action - inhibit conversion of dhf into tetrahydrofolate - prevents the synthesis of purines - high dose methotrexate txs. - administer lethal dose of methotrexate - few hours later, follw with folinic acid to rescue cells less dependent on purine synthesis. |
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topoisomerase inhibitors
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- topotecan
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inhibitors of microtubule function
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- vinca alkaloids
- taxanes - phase specific drugs ( M phase specific) |
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inhibition of mitosis
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- Vinca alkaloids (vinblastine) M phase specific
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vinca alkyloids
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- exert cytotoxic action by binding to alpha and beta tubulin, which are dimeric protein needed for forming spindle fibers along which the chromosomes migrate during mitosis. prevention of forming the spindle leads to an inability of cells to seperate the chromosomes during mitosis.
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taxanes (microtubule inhibitor)
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- binds to beta tubulin and prevents the dis assembly of microtubules.
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combination therapy
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- rationale - decrease resistance, increase tolerability and increase efficacy
- combine drugs with distinct - mech. of action - cell cycle phase activity - dose limiting toxicity |
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general adverse effects
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- changes to blood
- anemia (low red bc) - thrombocytopenia (low platelet) - leukopenia (low white blood cell - changes to GI tract - nausea - vomiting, diarrhea, anorexia, mucositis - other effects - opportunistic infections - alopecia - teratogenesis - secondary cancers |
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chemotherapy and drug resistance
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- primary resistance - unresponsive to the first exposure of tx.
- mutations of p53 tumor suppressor gene - compromised mismatch repair enzyme. - acquired resistance - develops in respons to anticancer tx. |
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acquired resistance ; develops in response to anti cancer tx.
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- resistance specific to the drug being applied by reducing uptake or increasing metabolism
- broad resistance to multiple drugs through increased MDR1 expression. MDR1 codes a cell surface transporter glycoprotein which enhances drug efflux from the cell. |
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biological response modifiers
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- anti angiogenesis
- hormone modifiers - vaccines - targeting oncogene products |
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angiogenesis and cancer
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- cancer - new blood vessels are required to allow tumor cells to escape into the circulation
- avastatin - prolongs survival in cancer patients by inhibiting vessel growth. |
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tamoxifen
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- estrogen can serve as a tumore promoter by triggering proliferation
- estrogen receptors (ER positive breast cancer ~70%) activated form = transcription factor. - selective estrogen receptor modulators - inhibit estrogen receptors - inhibit production of growth promoting hormones - early and advenced ER + breast cancer - prevention of breast cancer in women at high risk of developing the disease. - cytostatic - partial agonist at receptors in endometrium - increased risk for endometrial cancer. |
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tumore generating viruses
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- cervarix - is designed to prevent infection from HPV types 16 and 18
- types 16 and 18 are the cause (70% of the time) of cervical cancer (as well as some vaginal vulvar, anal, penile and oropharyngeal cancers) - Gardasil - is designed to prevent infection from HPV types 6,11,16 and 18. - types 16 and 18 are the cause of 70% of cervical cancer - types 6 and 11 cause genital warts in males and females. |
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vaccines
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- therapeutic vaccines - treat existing cancers by recruiting the immune system to target cancer cells by utilizing tumor specific proteins as antigens.
- a blood sample is taken from a patient in order to isolate dendritic cells, which deliver antigens to T cells and B cells, the lymphocytes that control the immune response. 2. the harvested dendritic cells are cultured with prostatic acid phosphatase, a recombinant protein found in 95% of prostate cancers. 3. the dendritic cells, now loaded with the antigen, are then injected back into the patient to trigger a reaction from the immune system. provenge - therapeutic vaccine approved by the fda for prostate cancer. - randomized, double blind, placebo controlled, multicenter trial showed an increase in overall survival by 4.1 months. |
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oncogenes
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- mamallian cell genes that promote cell proliferation and tumor growth and prevent programmed cell death.
- mutated or over expressed products stimulate mitosis even though normal growth signals are absent. - normal cells require growth factors ex. - platelet derived growth factor |
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platelet derived growth factor
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- growth factor stimulates receptor
- activates kinase - phosphorylates proteins - activation of transcription factors - entry into cell cycle - mutation results in growth factor independence so its constitutively activated kinase and leads to unregulated growth. |
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kinase inhibitors target oncogene products
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- BCR'ABL gene - protein is constitutively activ kinase
- occurs in 95% of leukemias - imatinib - clinical improvements in 50-95% of patients with chronic myeloid leukemia. - very selective - lower toxicity |
