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146 Cards in this Set
- Front
- Back
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What is pharamacology?
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Interations b/t drugs and living organisms
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What is pharmacodymnamics?
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effect of the drug on the body
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What is a ligand?
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endogenous/exogenous molecule that binds to receptor
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What is a drug?
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-exogenous moledcule that can alter the functions of the body, usually by ingteracting with a receptor
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What is a receptor?
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biological target (macromolcule) with which ligand/drug interacts to produce effects
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What is toxicology?
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-toxic interactions b/t drugs and living organisms
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What are various sources of drugs with examples?
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-natural products (paclitaxel, calcitonin, and penicillin G)
-synthetic (diazepenem) -semi-synthetic (amoxicillin) -biosynthetic (erythropoeitin) |
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What qualidfies the activity of sdrugs?
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modify existing biological functions
generally exert multiple effects |
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Whata re the roles of pharmacodynamics?
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-drugs usually interact witha receptor
-drugs must be present at mininum effective concentration -interaction must be of sufficent duration |
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What is the role of pharmacokinetics?
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-drug absorption into the blood
-drug metabolism into metabolites then transferered badck toi blood -drug distribution b/t blood and site of action (receptor binding-->biological activity) and other tissues/storage sites elimination of bdrugs from blood |
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Whata re the properties of drugs?
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-molecular weight
-lipophilicity/ polarity -stereochemistry (warfarin enatiomers) |
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What is the occupancy theory?
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-binding that cna be described by the following equilibrium:
drug +receptor<--> (drug-rteceptor)--> biological effect -biological response (efect is related to receptor binding -magnitude of effect is proportiaonal to receptor occupancy (stoichiometric) -maximal effect occurs when all receptors are occupied |
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What are binding assays (grind and bind experiments)?
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-measure receptor occupancy
-binding can be described by following equation: B= Bmax x C/ C+ Kd -add drug to tissue and measure total binding (specific and non-specific) and measurte non-specific binding, calculate difference (for specific binding) |
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Whata re functuional assays?
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-measures magnitude of biological response
-effect can be described by following equation: E=Emax x C/ C+EC50 -add drug to tissue bath with isolated tissue, use force transduceer to measuyre effect and record output |
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What is affinity?
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-probability that drug will bind to receptor
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What is intrinsic activity (efficacy)?
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-maximum effect achieved by binding of drug to receptor
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What is a full agonist?
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-produces maximal intrinsic activity
-defined as 1.0 |
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What is a partial agonist?
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-effect less than full agonist
-intrinsic activity <1.0 |
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What is non-stoichi0ometric binding and response (spare receptors)?
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-maximum effect achieved before all receptors are occupied
-EC50 is lower than Kd |
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What is antagonism?
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-combined effects of two drugs are less than expected
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What are antagonists?
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-have affinity to receptor, but no intrinsic activity
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What is surmountable (reversible, competitive) antagonism?
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-effect of antagonist can be overcome by increasing agonist concentration
-higher concentration of agonist required to produce a given effect |
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What is insurmountable (irreversible, non-competitive) antagonism?
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-effect of antagonist cannot be overcome by increasing agonist concentration
-maximal effect is reduced |
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What is potency?
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-dose of drug required to produce a given therapeutic effect
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What is efficacy?
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-maximum therapuetic effect that can be acheived by a drug
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What are quantal dose response relationships?
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-measure individual responses at each dose (all or none)
-plot cumulative percentage of subjects that respond vs. dose |
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What is median effective dose (ED50)?
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-dose required to produce desired response in 50% of subjects
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What is rthe median toxic dose (TD50)/ median lethal dose (LD50)?
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-dose required to produce toxicity or death, respectivly in 50% of subjects
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What is the therapuetic index?
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TD50/ED50 or LD50/ED50
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What is absorption? What realtionship does it have with biologial membranes?
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passage of drug from site of administration to bloodstream
-1. body is highly compartmentalized 2. for absorption to occur drug must move across membranes (tissue --> blood) |
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What is passive diffusion?
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1. no energy required
2. no carrier (non-saturable) 3. dependent on lipophilicity and Fick’s law |
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What is fick's law?
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flux across mebrane= (C1-C2)x (area x permeability coefficent)/ thickness
C1 & C2 = higher and lower drug concentrations, respectively area = surface area of tissue across which passive diffusion is occurring perm. coeff. = mobility of drug molecules in tissue thickness = thickness of tissue across which passive diffusion is occurring |
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What is active transport?
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1. energy required
2. carrier-mediated (saturable and inhibitable) 3. selective (important exceptions: P-glycoprotein, multidrug resistance proteins, others) 4. may function as influx or efflux pumps!! |
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What is faciliated diffusion?
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more important for endogenous molecules
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What is endocytosis?
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may be important for large molecules
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What is bulk flow (aqueous diffusion)?
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diffusion of water/solutes through pores in capillary vessels
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What are physiochemical properties of drugs that affect absorption?
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1. drug solubility/dissolution
2. lipophilicity 3. molecular weight 4. acid/base properties - ionization depends on pKa of drug and pH of tissue |
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What are physiological factors that affect absorption?
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1. anatomy of tissue
2. drug concentration at site of administration a. can alter concentration gradient across membrane b. effect of changing dose? 3. blood flow at site of administration a. can alter concentration gradient across membrane b. effect of tissue temperature? 4. presence of active transporters in tissue |
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How is the stomach and dudenum different in absorption of drugs?
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stomach:
-used fro digestion - thick (+mucus) -transit time is fast -surface area is small duadenum: -fuction is absorpotion -thin -slow stransit time -large surface area |
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What is enteral route of admission? parenteral? others?
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enteral: oral
parenteral: intravenous, intramuscular, subcutanous other: rectal, transdermal, pulmonary, sublingual/ buccal |
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What is oral admission of drugs?
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drug is taken by mouth
a. very common route presence of membrane-bound active transporters such as P-glycoprotein (Pgp) in GI tract -first pass effect involved |
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What are advantagous of oral drug admission?
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safe
useful for self-administration economical not painful |
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What are diasdvantages of drug admission?
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requires patient compliance
slow and/or variable absorption? destruction of drug in GI tract active transporters (see next page) first pass effect (see next page) |
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What is first pass effect?
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- metabolism in GI tract or liver may alter biological activity of drug
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What is rectal admission of drugs?
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a. useful when oral route is precluded
b. some first pass metabolism may occur c. mucosal irritation possible |
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What is intravenous admission of drugs?
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direct injection into a vein
a. drug must be perfused slowly |
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What is advantagous of intravenous admission of drugs?
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very rapid onset
accurate dosing useful for irritating/cytotoxic drugs? large volumes can be injected |
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What ios disadvantagous of intraveous injection of drugs?
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no recall
possibility of infection may not be suitable for lipophilic drugs adverse reactions possible (anaphylaxis?) |
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What is intramuscular admission of drugs?
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drug is injected directly into muscle
a. rate of absorption determined by blood flow to muscle b. can inject moderate volumes c. useful for moderately irritating drugs |
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What is subcutanous admission of drugs?
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drug is injected beneath the skin
a. absorption is usually rapid b. unsuitable for irritating drugs |
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What is transdermal (percutanous) admission of drugs?
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drug is absorbed through the skin
a. skin is very impermeable b. lipophilicity of drug very important c. controlled release patches d. systemic effects possible |
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What is pulmonary admission of drugs?
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drug is inhaled
a. useful for volatile anesthetics or aerosols b. absorption generally extensive and rapid c. size of aerosol particles important |
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What is sublingual/ buccal admission of drugs?
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under the tongue (sublingual) or in the cheek (buccal)
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What is intrathectal admission of drugs?
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- direct injection into region of spinal cord
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What is intraarterial admission of drugs?>
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direct injection into artery to target specific organ
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What is intraperitoneal admission of drugs?
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drug is injected into abdominal cavity (rare)
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What is intranasal admission of drugs?
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nasal cavity is well vascularized
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What is drug distribution?
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bidirectional movement of drug from blood to its site(sd) of action or storage
-involves movement across membranes -similar transport mechanisms as absorption |
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What is bioavailability?
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-extent to which drug reaches its site of action
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What are physicochemical properties of drug distribution?
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-lipophilicity (including acid/base properties)
-molecular weight |
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What are physiological factors of drug distribution?
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-tissue/capillary permeability
-plasma protein binding -blood flow through tissue -presence of active transporters in tissue |
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How is tissue/capillary permeability a physiological factor of drug distribution?
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-most capillary vessels are highly permeable via bulk flow (aqueous diffusion)
-tight junctions and active transporters in CNS capillaries constitue "blood brain barrier" |
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How is plasma protein binding a physiological factor of drug distribution?
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-major plasma proteins include serum albumin (acidic drugs) and alpha 1-acid glycoprotein (basic drugs)
-binding is reversible -only unbound fraction of drug undergoes distribution |
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How is blood flow through tissue a physiological factor of drug distribution?
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-rapid to highly perfused tissues (heart, kidney, liver)
-diffusion into interstitual space also rapid |
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How are drugs distributerd across placenta?
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-consists of maternal and fetal tissue
-no barrier for lipophilic drugs -some drugs must be avoided during pregnancy |
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What are examples o drug reservoirs?
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-plasma proteins
-cellular reservoirs (cellular binding and active trasnport) -adipose tissue (accumulation of lipophilic drugs and stable reservoir) -bone/teeth (release is very slow amd effects cam be persistent |
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What is drug metabolism (biotransformation)?
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-chemical modification of drug molecule
-usually converted to more polar forms to enhance elimation -has effect on biologicval activity |
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What is the biological effect of the metabolite of chloral hydrate? the parent drug?
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-sedative/hypnotic
-inactive |
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What is the biological effect of the metabolite of phenobarbital? "parent drug"?
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-inactive
-sedative/hypnotic |
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What is the bioloigical effect of the metabolite of aspirin? parent drug?
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-analgesic
-analgesic |
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What is the biological effect of the metabolite of acetaminophen (overdose)? parent drug?
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-toxic (liver)
-analgesic |
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What are phase I reactions of metabolism?
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-attach small polar functional groups
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What are phase II reactions of metabolism?
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-attach small polar molecule
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What organs are sites of metabolism?
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-liver
-other tissues (extrahepatic sites) |
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What subcellular organelles are sites of metabolism?
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-microsomes- most phase I enzymes
-cytosol- most phase II enzymes |
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What is cytochrome P450?
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-microsomal
-present in may organs -has multiple forms -catalyzes hydroxylation of drugs (and other reactions) such as warfarin -used in Phase I metabolism |
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What are the various isozymes of cytochrome P450 from most contribution to least?
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-CYP3A4-54%
-CYP2D6-30% CYP2C9/CYP2C10/CYP2C19-11% CYP1A2-4% -CYP2E1-2% |
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How does alcohol metabolism work?
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-converted tyo aldehydes then to catboxylic aqcids
-sequentially catalyzed by two enzymes (cytosolic)- alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (AIDH) -occurs in liver -phase I metabolism |
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how does hydrolysic of esters and amides work?
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-H2O is added to substrate
-catalyzed by esterases (ester hydrolysis) or amidiases (amide hydrolysis) -occur sin liver, kidneys and plasma -Phase I metabolism |
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How does glucuronidation work?
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-glucoronic acid is transferred to substrate
-catalyzed by UDP-gluconosyltranferases (microsomal) -common metabolic transformation -phase II metabolism |
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How does sulfation work?
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-sulfate ion is transferred yo substrate
-catalyzed by sulfotransferases (cytosolic) -phase II metabolism |
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How does glutathione conjugation work?
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-glutathione (Glu-Cys-Gly) is transferred to substrate
-catabyzed by glutathione transferase (cytosolic) -"proptective" process since substrates are often reactive, toxic molecules (most glutathione conjugates are non-toxic) -further metabolismn produces "mercapturic acids -phase II metabolism |
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How does acetylation work?
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-acetyl group is transferred to substrate
-catalyzed by N-acetyltransferases (cytosolic) -phase II metabolism |
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How does amino acid conjugation work?
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-amino acid is trasnferred to the substrate
-relativly uncommon -catalyzed by amino acid acytltransferases (mitochrondrial and cytosolic) |
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Whata re various factors that affect drug metabolism?
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-enzyme induction
-enzyme inhibiton -species -age -gender -genetic polymorphism -route of administration -disease status |
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What is enzyme induction? How does it effect biological activity? Examples?
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-increased biosynthesis of enzyme
-increased drug metabolism -phenobarbital -polycyclic aromatic hydrocarbons (present in cigarette smoke) -other drugs, ethanol, steroids -drug-drug interaction possible |
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What is enzyme inhibition? Effect on biological activity
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-enzyme activity inhibited
-decrease enzyme development |
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How do species affect drug metabolism?
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-wide variations in metabolic capabilities occur
-different pathways, different metabolites -like acetominophen toxicity in cats |
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How is age a factor in drug metabolism?
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-different forms of cytochrome in fetus and adult
-need to give differnt doses for elderly and infants -smaler doses for infants |
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How is gender a factor in drug metabolism?
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-common differences in rodents
-some in humans |
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What is genetic polymorphism?
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-inherited metabolic differences (enzyme lvls, enzyme act, etc) exists b/t human races
-aceylation is affected based on race -cytochrome p450 (CYP2D6 ) is hihgly polymorphic |
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What is the effect of liver disease on drug metabolism?
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-cirrohis and cancer won';t let liver metabolize drugs
-becomes toxic |
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What is drug elimination (excretion)?
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-removal of the drug from the body
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What is half-life?
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-time required for plasma concentration to decrease by 50%
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What are the major sites of excretion? minor?
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major- kidneys, liver (bile), and lungs
minor- breast milk, sweat, saliva, and hair |
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What is glomerular filtration?
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-passive process
-plasma protein-bound drugs are not filtered, decreases elimination (warfarin) |
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What is tubular reabsorption?
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-passive process
-dependent on lipophilicity of drug and pH of tubular fluid |
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What is tubular secretion?
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-active transport system for acids and bases
-ex: penicilin -bidirectional (blood<--> tubular fluid) |
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How do you alter renal elimination rate?
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-by altering urine pH
-by inhibiting active transport/tubular secretion (probecid +penicillin-->decrease excretion of penicillin) -renal disease (decrease blood flow--> decrease excretion--> increase plasma levels) adjust dosage to compensate |
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What is the mechanism of biliary elimination?
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-metabolites formed in liver may be secreted into circulation or bile
-may be excreted in feces ir reabsorbed into GI tract -intestinal enzymes can alter reabsortion -enterohepatic recycling can occur which increases half-life |
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What cna alter biliary elimination?
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-liver disease
-some drugs can alter bile flow -antibiotic--> decrease GI bacteria--> decrease recycling |
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What is drug-drug interation?
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-change ina ctivity due to presence of other drugs
-problem for drugs with narrow therapeutic index -has beneifical and detrimental effects |
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What is pharmacological antagonism?
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-competition for same receptor
-ex: morphine (agonist) +naloxone (antagonist) |
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What is functional antagonism?
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-produce biologically opposite effects (acetylcholine and epinephrine)
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What is chemical antagonism?
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-combine to form an inactive compound (dimercaprol +heavy metals (arsenic, mercurym etc)
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How do drug-drug interactions affect absorption?
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-formation of complexes may impair absorption from GI tract (such as tetracycline +antacids)
-effect of food -inhibition of active transporters |
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How does drug-drug interaction affect distribution?
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-displacement from binding sites on plasma proteins (warfarin +aspirin)
-inhibition of active transporters |
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What does phenobarbital induce? ethanol (chronic)? omeprazole and cigarette smoke? rifampin, sulfinpyrazole, and st john's wort?
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-multiple CYP isozymes and UDP-glucuronsyltransferase
-CYP2E1 -CYP1A2 -CYP3A4 |
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What does cimetidine, erythromycin, and omeprazole inhibit? Ethanol (acute)? doxorubicin? sulfinpyrazone? ketoconazole and grapefruit juice?
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-multiple CYP isozymes
-CYP2E1 -CYP2D6 -CYP2C9 -CYP3A4 |
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How does drug-drug interaction affect elimination?
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-inhibition of tubular secretion (penicillin +probenecid)
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What is the general background of cancer? How would you treat it?
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-second leading cause of death due to disease in the US
-estimated 1,437180 new cases in 2008 -trezt using antineoplastic agents (chemotherapy) -surgery -radiation |
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What are characteristics of cancer cells in contrast to normal cells?
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-increased proliferation rate
-loss of differentiation -potential for metastasis (ability to spread beyond its origin |
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What is the cell cycle of tumor growth?
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-protein synthesis
-DNA synthesis -premitosis -mitosis -resting phase |
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What are alkylating agents?
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-converted to reactive compounds (i.e. carbonium ions)
-form covalent bonds with DNA (alkylate bases--> DNA cross-links) -cytotoxicity (cell death) may result from inhibition of DNA replication and function -cell cycle nonphase specific agents (damages cells no matter the phase they're in) |
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What are examples of nitrogen mustards (alkylating agent)
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-mechlorethamine
-cyclophosphamide |
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What do alkylating agents do?
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-primary target is DNA alkalation agents
-such as electrophiles (e- defincient molecules) -goal is to stop replication, damage DNA unable to functional transcribe, etc |
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What is mechlorethamine as a alkylating agent? mechanism of action? natural substrate? clinical use? Toxicity?
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-nitrogen mustards
-highly unstable compound (iv dosing) -alkylates two guanines in DNA (bifunctional) -may enter cells by active trasnport (natural substrate is choline) -clinically used for Hodgkin's lymphoma -myelosuppression, 2 degree cancers (carcinogenic) |
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What is cyclophosphamide as a alkylating agent? mechanism of action? clinical use? toxicity?
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-widely used alkylating agent
-stable compound- cna be taken p.o. or i.v. -parent compound is inactive ("prodrug") -metabolized by CYP isozymes in liver then rearranges to phosphoramide mustard (active alkylating agent) -clinically used as broad spectrum of activity (for leukemias, lymphomas, solid tumors) and can be given orally -causes myelosuppression, hemorrhagic cystitis (due to acrolein) |
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What are nitrosoureas as an alkylating agent? mechanism of action? clinical use? toxicity?
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-include Iomustine (CCNU) and carmustine (BCNU)
-lomustine admin. orally -carmustine admin. by IV -highly lipophilic- can readily cross the blood brain barrier (treats brain tumors) -alkylates DNA, RNA, and proteins -clinically used to treat lymphomas and brain tumors -can casue myelosupression, nausea/vomiting |
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What are platinum containing compounds as alkylating agents? mechanism of action? clinical use? toxicity?
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-includes cisplatin, carboplatin, and oxaliplatin
-lipophilic- enters via passive diffusion -alkylates DNA (crossilinks) -clinically used as broad spectrum of activity against lymphomas and solid tumors -cna casue neurotoxicity/nephrotoxicity (cisplatin), myelosupression (carboplatin), and reversible nephortoxocity (oxaliplatin) |
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Whata re the differences in genreations between the paltinum containing compounds?
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-1st generation is a prototype of the class, despite bveing good when treating
-extremely toxic -2nd generation tried to conatin anti-cancer activity but altered to try to reduce toxcitiy -by altering and finding subsequent generations, have been able to alter toxicity |
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What are antimetabolites? Examples?
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-analogues of normal cell metabolites
-active in S-phase of cell cycle (interfering with DNA adn RNA synthesis) -folic acid antagonist -purine antagonist -pyrimidine antagonist |
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What is the folic acid antagonist as an antimetabolite? mechanism of action? clinical use? toxicity?
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-folic acid is an enseential vitamin
-active fvrom is tetrahydrofolic acid -cofactors required for biosynthesis of DNA, RNA, amini acids -methotexate is analogue of folic acid -MTX intervferes with deoythymidylate synthesis via inhibition of dihydrofolate reducatase -actively trasnported into cells -MTX and folate cofactors undergo polyglutamylation in cells -clinically used for broad spectum activity and non-neoplastic disease -combination with leucovorin allows higher (toxic) doses of NTX to be used -causes myelosupression and GI tract, renal tubular damage |
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What are purine antagonists as an antimetabolite? mechanism of action, clincial use? toxicity?
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-6-mercaptopurine and 6-thioguanine are analoues of hypoxanthine and guanine respectivly
-inhibits pruine biosynthesis at cellular level and then ultimatly inhibit DNA synthesis -clinically used against leukemias -cuases myelosupression |
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What is polyglutamylation?
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-cell will keep adding glutamic acids into the end of MTX with folate co-factors
-this can be a good advantage becasue the long chain of glutamic acids will chang epolarity (in creases which now limits the cells ability to leave the cell -chain makes cofactors better/ more efficient |
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What are the pyrimidine antagonists?
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cytarabine
-flourouracil |
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What is flourouracil as a pyrimidine antagonist? prodrug? mechanism of action? how is it administered clinical use? combination therapy? toxicity?
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-analogue of uracil
-converted tintracellularly into flourdeoxyuridine monkiphospate (fdUMP) -FdUMP interfereds with deoxythimdylate ()dTMP) synthesis via irreversible inhibition of thymidylate synthase -administered parenterally due to erratic absorption in GI tract or topically -clinically cused against solid tumors and basal cell carcinomas -combination therapy with leucovorin enhances cytotoxicity of 5-FU -can casue myelosuppression and GI tract damage |
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What is a pordrug?
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-biologically inactive until it undergoes metabolism in the body
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What is cytarabine as a pyrimidine antagonist? prodrug? mechanism of action? how is it administered? clinical use? toxicity?
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--analogyue of deoxycytidine
-converted intracellularly into cytarabine triphosphate -incorporated into DNA and inhibitis chain elongation -also inhibits DNA polymerase (high concentrations only) -administered parenterally due to poor absorption in GI tract -clinically used for leukemia -causes severe myelosuppression |
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What are tubulin active drugs? Examples?
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-alter the structure or formation of microtubules
-disrupt polymerixzation<--> disaseembly -active in M-phase of cell cycle -vinca alkanoids -taxoids |
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What are vinca alkaloids as a tubulin active drug? mechanism of action? clinical use? toxicity?
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vincristine, vinblastine, and vinorelbine are examples?
-interferes with mitosis -binds to tubulin and inhibit microtubule formation (polymerization) -mitotic arrest results in cytotoxicity -clinically used for lymphomas, breast cancer (vinblastine), leukemias and lymphomoas (vincristine), lung and breast cancer (vinorelibine) -can cause myelosuppression (vinblastine), neurotoxcicity (vincristine) and myelosuppression (vinorelibine) |
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Whata re taxoids as a tubulin active drug? mechanism of action? clinical use? toxicity?
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-paclitaxel and docetaxel are examples
-interferes with mitosis -inhibits microtubule disassembly and promote formation of stable, but non-functional mitotic spindle -mitotic arrest results in cytotoxicity -clinically used for broad spectrum of activity -cna casue myelosuppression and neurotoxicity (paclitaxel) |
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What are topoisomerase inhibitors? Examples?
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-involved in DNA "unwinding"-->replication
-active in S/G2- phases of cell cycle -epipodophyllotoxins -anthracycline antibiotics -campotothecins |
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What are epipodophyllotoxins as a topoisomerase inhibitor? mechanism of action? clinical use? toxicity?
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-etoposide and teniposide are semi-synthetic derivatives of podophyllotoxin
-inhibits topoisomerase II (involved in DNa unwinding) -topoisomerase II produces transient double-stranded DNA breaks -inhibition of religion--> DNA fragmentation--> cell death -clinically used for broad spectrum (etoposide) and leukemias (teniposide, limited use) -causes myelosuppression and 2nd degree leukemias |
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Whata re anthracylcine antibiotics as a topoisomerase inhibitor?
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-doxorubicin and daunorubicin and idarubicin are examples
-inhibits topoisiomerase II -intercalation into DNA double helix -generation of highly reactive free radicals--> cardiotoxicity! |
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What are campotothecins as topoisomerase inhibitors? mechanisms of action? clinical use? toxicity?
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-irinotecan (prodrug) and topotecan are semi-syntyhetic plant products
-inhibits topoisomerase I -inhibiton of religation--> DNA fragemntation--> cell death -clinically used for colorectal cancer (irinotecan, lung and ovarian cancer (topocecan) -causes myelosuppression and severe diarrhea (irinotecan) |
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-Whata re hormonal agents? examples?
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-tumor growth may be hormone-dependent
-active in G1-phase of cell cycle -selective estrogen receptor modulators (SERMs) -aromatase inhibitors |
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Whata re selective estrogen receptor mudlators (SERMs) as hormonal agents? mechanism of action? clinical use? toxicity?
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-tamoxifen and toremifene
-estrogen antagonism -ligand binding to ER triggers dimerization and conformational change -ER-ligand dimer binds to estrogen responsive element (ERE) -coavtivators or corepressors also bind -clinically used for ER (+) breast tumors in post menopausal womena nd men, preventative activity in susceptible women -generally mile toxicity, has increased risk in endometrial cancer, blood mclots and stroke |
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Whata re aromatase inhibitors as hormal agents? mechanism of action? clincal use? toxicity?
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-anastrazole, letrozole are non-steroidal, reversible inhibotrs and exemestane is a stereoidal, irreversible inhibitor
-estrogen depletion via inhibitoon of aromatase (CYP19) -clinically used for breast cancer in post-menopausal women -can have loss in bone mineral density and musucloskeletal effects (neuralgia and myalgia) |
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Whata re epidermal growth factor receptor antangoists used in targeted therapies?
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-important for cell proliferation
-EGFR is overexpressed in a variety of human cancers -activation of EGFR in tumor cell--> tumor growth -ligand (epidermal growth factor ) binds to extracellular doman -domain forms dimer with another receptor unit intrinsic tyrosine kinase activity autophorphorylates intracellular domain -intracellular signaling pathways are activated and tumaor growth is stimulated |
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What is the mechanism of action of epidermal growth factor receptor antagonism?
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-extracellular domain is monoclonal antibodies (cetuximab)
-intracellular domain is "small molecule" tyrosine kinase inhibitors such as gefitinib and erlotinib -clinically used for colon, head, adn neck tumors (cetuximab), non small cell lung cancer and other small solid tumors (gefitinib and erlotinib) -causes allergic reactions and skin rash (cetuximab), diarrhea and skin rask (gefitinib and erlotinib) |
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How are angiogenesis inhibitors used in targeted therapies?
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-tumor growth usually requires formation of new blood vessels (angiogenesis)
-angiogenesis is dependent on proteins such as vascular endothelial growth factor (VEGF) and platelet-dereives grwoth factor (PDGF), etc -hypoxic tumor cells secrete VEGF, PDGF, etc -VEGF binds to VEGF receptor on endothelial cell surface -blood vessel growth stimulated--> tumor growth stimulated -cellular target is vascular endothelial cells |
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What is the mechanism of action for VEGF/PDGF receptor antagonists for targeted therapy?
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-ligand is monoclonal antibodies (bevacizumab) (binds to VEGF)
-intracellular domain is small molcule tyrosine kinase inhibitors (sunitinib)(VEGF/PDGF receptor antagonist) -clinically used for solid tumors (colorectal, renal cell, GI, etc) -causes hypertension, thrombosis, and diarrhea |
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Whata re other monoclonal antibodies (MABs)? mechanism of actiuon? clincial uses? toxicity?
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-target specific antigens on surface of tumor cells
-binding of MAb to antigen triggers response -rituximab's antigen is CD 20 which is primarily expresses on B-lyphoycytes -can be clinically used for CD20 posisitive B-cell non-Hodgkin;s lymphoma -can casue infusion reaction, tumor lysis syndrome, and cardiovascular damage -trastuzumab's antigen is HER2 which is overexpresed in 25-30% of human breast cancers -clinically used for HER2-positive metastatic breast cancer and other tumors -can cause myelosuppression, infusion reactions and cardiovascular damage |
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What is resistance to antineoplastic agents?
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-100% kill of sensitive cells is not possible
-restant cells that survive chemotherapy may result in tumor regrowth -multidrug resistance (MDR) to different drugs can occur |
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What is decreased drug influx as a mechanism for resistance to antienoplastic agents? increased drug efflux? altered receptor binding? altered drug metabolism? increased DNA repair?
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-decreased folate trasnporter-reduced uptake of MTX
-Pgp overexpression (sctivly pumps drugs from cell) and decreased glutamylation (increased MTX efflux) -increased DHFR lvls (overcomes inhibiton by MTX) and altered DHFR (lower affinity for MTX) -dcreased convesion of 5-FU to FdUMP and decreased conversion of araC to araCTP -alkylating agents ( alkyl groups removed from DNA) |
