Pmcol 344 Flashcards
GIT OTC preparations
laxatives
antacids
gas relievers
anti-diarrheals
hemorrhoid tx
GIT endocrine system
90% of body’s serotonin
50% of body’s dopamine
gastrin
ghrelin
cholecystokinin
layers of GIT
mucosa
submucosa
muscularis
serosa
mucosa layer
epithelium
lamina propria
muscularis mucosae
submucosa layer
submucosal plexus
muscularis layer
circular muscle
myenteric plexus
longitudinal muscle
ENS
intrinsic neural network within walls of GIT
regulates motility, secretion, local blood flow, and immune responses
integrated with + regulated by ANS; acts independent of CNS
submucosal plexus
innervates epithelia + muscle cells
myenteric plexus
regulates gut motility + secretion
lies between muscle layers
ENS fibres
receives vagal psymp ACh = excitatory
- ↑ gut motility, dilate sphincters, ↑ secretions
receives symp NA
- ↓ gut motility = ↑ absorption, constrict sphincters
sensory nerves signaling mech. + chem. stimuli
mediates spinal + brainstem refleces regulating digestive function
provides input to central autonomic circuits that regulate feeding + illness behaviours
transmit both painful + non-painful sensation
gut motility
peristalsis + segmentation
determined by smooth muscle properties and modified by chemical inputs (nerves, hormones, paracrine signals)
different regions = different types of motility due to enzymes and pH differences
- sphincters → tonic contractions
- small intestine → phasic contractions
peristalsis
propulsion of food from mouth to anus (aborally)
involves coordinated contraction + relaxation
segmentation
mixes food to facilitate digestion = more surface area of food for acid + enzymes to act on
mixes contents over a short length of intestine
small intestine motility
rhythmic electrical activity accompanies contractions
phasic activity driven by slow waves
propagation slows with more distal segments
when slow wave reaches threshold, v.g. Ca2+ ch open → influx = APs fire + mm. contract
peristaltic reflex
triggered by mechanical stretch + mucosal stimulation
activates excitatory motor neurons above bolus (enterochromaffin cells release 5HT → stimulates sensory nn. in myenteric plexus)
activates inhibitory motor neurons below bolus = relaxes gut wall
gastrin
made in mucosal enteroendocrine cells
stimulates acid secretion by parietal cells in stomach = ↑ digestion
5HT
from enterochromaffin cells
release triggered by food constituents, stretching of gut wall; endogenous mediators ex. gastrin
increases ACh release from ENS nerves
motilin
from mucosal cells
stimulates contraction of GI smooth muscle
cholecystokinin
from small intestine enteroendocrine cells
stimulates pancreatic enzyme secretion
glucagon-like peptide 1
stimulates insulin release, inhibits glucagon release
promotes satiety
enteroendocrine cells
respond to nutrients, NTs, local signals to release hormones
gastric secretions
human stomach secretes ~2.5 L gastric juice per day
acidity promotes proteolysis, kills pathogens, aids in iron absorption
peptic Chief cells
secrete pro enzymes - prorennin, pepsinogen
parietal cells
secrete 150 mM HCl = pH ~ 1-2
active secretion of Cl- + K+
H+/K+ ATPase pumps K+ into cell and H+ into lumen
carbonic anhydrase generates H+ and HCO3- from H2O and CO2
HCO3- exchanged for Cl- by antiporter
protective mechanisms of stomach wall
mucosal cells secrete prostaglandins (PGE2 + PGI2)
- mucosal cell EP4 Rs = stimulates mucus secretion + EP1/2 Rs = secretion of bicarbonate ions
- ECL cell EP2/3 Rs = inhibit histamine release = ↓ acid release via H2 receptors
- vascular EP2/4 Rs = vasodilation → improve blood flow to mucosal layer
stimulation of HCl secretion
- histamine (released basally from ECL cells) acts on H2 Rs on parietal cells = activate proton pump via Gs, cAMP
- gastrin (secreted by G cells in response to nerve stimulation + stomach contents) acts on CCK2 Rs on ECL cells → ↑ Ca2+ = release of histamine
- ACh (released from postG cholinergic neurons) acts on parietal cell M3 Rs to stimulate proton pump via elevation of Ca2+; inhibits somatostatin release from D cells
inhibition of HCl secretion
- prostaglandins inhibit histamine production, ↑ HCO3- + mucus secretion, vasodilation
- tonic release of somatostatin from D cells in stomach → acts on SST2 Rs on G cells to inhibit gastrin release, ECL cells to inhibit histamine release, parietal cells to inhibit acid secretion
ulcer
bleeding, perforation leading to stomach contents entering body cavity and causing peritonitis
fatal without intervention
GERD
damage to esophageal epithelium
can lead to Barrett’s esophagus (precancerous)
hiatal hernia
similar problem to GERD
esophageal acid reflux
causes of ulcers
- stress: vagal stimulation = ↑ ACh release = ↑ HCl
- COX inhibition by NSAIDs = ↓ production of protective mucosal PGs
- H.pylori infection → 80-90% of gastric ulcers, 95% of duodenal ulcers
H.pylori infection
primary cause of ulcers
corkscrew-shaped, gram (-) bacteria
present in ~50% of pop → causes peptic ulcer disease in ~20%
gastritis: asymptomatic inflammation of the stomach lining → ulcers → cancer
class 1 carcinogen
burrow into stomach mucus lining = damage allows acid + pepsin to reach epithelium
releases urease → converts urea to HCO3 + ammonia = neutralize acid (forms buffer zone to protect bacteria)
produces toxins that kill epithelial cells
local infl: immune cells spill destructive agents on stomach lining cells
therapeutic goals of ulcer tx
relieve sx
allow damaged tissue to heal
eliminate cause
urea breath test
drink solution containing 13C/14C labelled urea
collect exhaled breath → if CO2 is labelled, indicates H.pylori presence
quick, cheap, non-invasive
tx for ulcers/GERD/hiatal hernia
- antibiotics
- ↓ gastric acid secretion
- neutralize secreted acid
- protect mucosa
Triple Therapy
combination of proton pump inhibitor and antibiotics
Omeprazole + Clarithromycin + Amoxicillin
tx for 2 weeks
cure if ulcer caused by H.pylori
proton pump inhibitors
↓ acid secretion
first line therapy
prodrugs → active binds covalently to cysteines in active site of H+/K+ pump
inhibits both basal + stimulated acid secretion
H2 receptor antagonists
↓ acid secretion
selective competitive orthosteric antagonists at H2 receptors on parietal cells = inhibition of histamine + gastrin stimulated acid secretion
antacids
neutralize acid
basic inorganic salts taken orally to neutralize gastric acid + inhibit peptide enzymes
chemical antagonism
not absorbed
mixture of magnesium + aluminum hydroxide to balance bowel fxn
mucosa protectors
enhance endogenous mucosal protective mechanisms / provide physical barrier over ulcer
nausea
feeling of impending vomiting
harder to control pharmacologically
vomiting
emesis
forceful evacuation of gastric contents through mouth
physiological response to
- irritating substances in hut or blood stream
- excessive vestibular stimulation
- psychological stimuli
emetic drugs
induce vomiting to prevent absorption of ingested toxic substances
anti-emetic drugs
useful bc vomiting reduces effectiveness of tx, can cause dehydration + nutrient depletion
- mAChR antagonists
- 5HT3 R antagonists
- D2 R antagonists
Chemoreceptor trigger zone
BBB is permeable = allows circulating emetogenic mediators to act
receives inputs from vestibular nuclei + directly fro GIT
activates neurons in vomiting centre
D2 + 5-HT3 receptors
vomiting centre
receives impulses from CTZ, GIT, + higher cortical centres
coordinates physical act of vomiting
mACh receptors
vestibular nuclei
inputs from labyrinth (inner ear)
H1 + mACh receptors
diarrhea
frequent passage of liquid feces
may be accompanied by abdo cramps + nausea
phycl mech to rid gut of irritating substances
caused by infection, anxiety, drugs, inflammatory disease
primary cause of death in infants in developing countries
results from disordered water + electrolyte transport in small intestine = ↑ gut motility, ↑ fluid secretion, ↓ fluid absorption = loss of electrolytes + H2O
intestinal fluid balance
consume >2 L of fluid daily
saliva + secretions from stomach, pancreas, liver add 7L = 9L enter small intestine
H2O + electrolytes are absorbed in intestine + secreted in bowel → ~1L reaches large intestine (exceeds capacity = diarrhea)
only 100-200 mL of H2O excreted
water absorption
in small intestine (epithelial cells express ion channels, pumps, + transporters on luminal + basolateral membranes)
caused by osmotic gradients created when solutes are absorbed from lumen
Na+ enters cells → transported into ECF by Na+/K+ ATPase
= ↑ ECF osmolarity → H2O follows passively through aquaporins
water secretion
in small intestine
NaCl is transported from ECF into epit cells
Na+ is pumped back into ECF by Na+/K+ pump; Cl- passes into lumen via CFTR channel
= osmotic gradient → H2O follows passively via intercellular channels
secretory diarrhea
abnormal secretion of H2O + salts into small intestine
impaired absorption of Na+; normal/↑ Cl- secretion
= net fluid secretion → loss of H2O + salts
causes dehydration
may be caused by bacteria ex. cholera irreversibly activates CFTR = constant Cl- efflux
osmotic diarrhea
due to ingestion of poorly-absorbed, osmotically active substance ex. sorbitol, mannitol
H2O moves from ECF into lumen to balance osmolarity
= ↑ vol of stool → dehydration due to H2O loss
looser coupling bw mvt of NaCl + H2O (H2O loss > NaCl loss = hypernatremia)
tx of diarrhea
- oral rehydration (H2O + electrolytes; add glucose to enhance absorption)
- anti-infective agents (if bacterial infection)
- spasmolytics
- adsorbents
bacterial infections causing diarrhea
E.coli
salmonella
shigella
campylobacter
= treat with anti-biotics
spasmolytics
tx of diarrhea:
relaxation of gut smooth muscle = ↓ gut motility = ↑ transit time = ↑ time for reabsorption of water
- muscarinic antagonists
- opioid receptor agonists
muscarinic antagonists (tx of diarrhea)
block action of ACh (primary stimulatory NT in gut = contraction, propulsion)
= relax gut muscle → ↓ motility
side effects significant (widespread action) = rarely used
opioid receptor agonists (tx of diarrhea)
activate opiate receptors = affect motility, secretion, + transport of electrolytes + fluid
primary site of action: ENS inhibitory preS receptors = ↓ ACh release
= ↑ segmentation + ↓ peristalsis
↑ transit time so water absorption ↑
symptomatic relief
adsorbents (tx of diarrhea)
bind up H2O in gut = ↓ mvt
symptomatic relief (does not ↓ dehydration; efficacy unclear)
ex. kaolin, pectin, chalk, charcoal, methylcellulose
potentially adsorb pathogens/toxins; coat + protect mucosa
constipation
slowed passage of food through GIT
50+% of people affected
causes: drugs (opiates, antidepressants, iron supplements); diet, hydration state, exercise; hormones, IBS
purgatives
accelerate passage of food through intestine + evacuation of bowels
bulk laxatives, osmotic laxatives, stimulating purgatives, stool softeners
used to relieve constipation or to clear bowel prior to surgery/examination
prolonged use can lead to dependence
agents that ↑ GIT motility without purgation
cholinomimetics
D2 antagonists
5HT-4 agonists
bulk laxatives
ex. methyl cellulose, ispaghula husk
polysaccharide polymers that are not broken down by digestion in upper part of GIT
form bulky hydrated mass in gut lumen
mechanical distension promotes peristaltic reflex
slow action but no absorption = no unwanted effects
osmotic laxatives
ex. lactulose
poorly absorbed = produce osmotic load in lumen → draws water into gut lumen
softens stool + stretches gut to promote peristalsis + defecation
takes 2-3 days to act but not absorbed = no unwanted effects
stimulant laxatives
↑ electrolyte + water secretion / ↑ peristalsis
ex. bisacodyl, senna
cholinomimetics (tx of constipation)
muscarinic agonists + cholinesterase inhibitors
enhance GI contraction but uncoordinated → little/no net propulsive activity
dopamine in GIT
GIT produces 50% of body’s DA
see changes in GI fxn in Parkinson’s
DA modulates gut motility by mediating neg feedback mechanism → released at same time as ACh during peristalsis to cause muscle relaxation + inhibition of ACh release
D2 receptors on preS ACh termines + postS muscle
D2 antagonists (tx of constipation)
block effects of endogenous dopamine (no effect on ACh = normal release)
inhibit smooth muscle relaxation and enhance ACh release = ↑ contractility + peristalsis
actions are negated by anticholinergic drugs (little effect if muscarinic Rs are blocked) → preS D2R effect is more important than postS
5HT-4 agonists
tx of constipation
preS 5HT-4 Rs in myenteric plexus = ↑ ACh release
Irritable bowel syndrome (IBS)
unknown cause, possible: alterations in 5HT reuptake, bacterial infection, hormones
not inflammatory bowel disease
alterations in GIT motility
constipation, diarrhea, mixed, unspecified
IBS tx
symptomatic
- diet
- stress management
- laxatives/anti-diarrheals
(PG analogues)
Ulcerative colitis
inflammatory disorder causing ulcers in lining of rectum + colon
inflammation → cell death = ulcer
infl in colon = frequent emptying → diarrhea
associated w ↑ risk of cancer
Crohn’s disease
inflammatory disorder
infl deeper in intestinal wall; not exclusive to colon → along entire GIT
associated w ↑ risk of cancer
tx for UC / Crohn’s
long term tx with anti-inflammatory / immunosuppressant drugs
- anti-diarrheals (treat sx)
- glucocorticoids = anti-infl + immunosuppressants
- aminosalicylates
- biopharmaceuticals (humanized antibodies)
hemostasis
dynamic process
vascular injury
platelet adhesion
platelet aggregation
fibrin formation (coagulation)
fibrinolysis
vascular repair
thrombosis
pathological formation of hemostatic plug
often occurs in absence of bleeding
= clot formation
white clots
arterial (rapid blood flow) → heart + brain
composed of platelets, some fibrin
main risk factor = ruptured atherosclerotic plaque
clinical presentation = MI, cerebrovascular stroke
tx: anti-platelet drugs
red clots
venous (relative stasis) → veins, heart chambers
composed of fibrin + RBCs, few platelets
main risk factor = slow/disturbed blood flow; hypercoagulable state
clinical presentation = venous thromboembolism, cardioembolic stroke
tx: anticoagulant drugs
prevention of blood clots
antiplatelet drugs
anticoagulant drugs
treatment of blood clots
thrombolytic/fibrinolytic drugs
anti-platelet drugs
ASA
thienopyridines
non-thienopyridine P2Y12 antagonists
Dipyridamole
GP IIb/IIIa R antagonists
prevent platelets from aggregating = prevention of adverse CV events or stroke
inhibit platelet aggregation by targeting platelet pathways
platelet signaling
platelet activation → release ADP + TXA2 → activate GP IIb/IIIa + fibrinogen binding → aggregation
ASA
COX inhibition = prevents TXA2 synthesis
Thienopyridines
orally active prodrugs requiring hepatic conversion to active metabolites
irreversible non-competitive antagonists of ADP binding to P2Y12 receptors
= stop aggregation + secretion of infl. mediators
ticlopidine, clopidogrel, prasugrel
Non-thienopyridine P2Y12 antagonist
Ticagrelor
same target as thienopyridines but different mechanism (reversible allosteric antagonist)
Dual Anti-Platelet Therapy
ASA combined with P2Y12 inhibitors (usually Clopidogrel, or Ticagrelor)
up to 1 year following MI, 1 month following cerebrovasc stroke
Dipyridamole
inhibits phosphodiesterase = prevent breakdown of cAMP/cGMP
enhanced inhibition of platelet aggregation
glycoprotein IIb/IIIa antagonists
block receptor for fibrinogen or compete for occupancy
inhibit final common step leading to platelet aggregation
IV administration - prevent thrombosis in pts with acute coronary syndromes or undergoing coronary angioplasty
unwanted effects: bleeding, thrombocytopenia
abciximab, eptifibatide, tirofiban
blood coagulation
secondary hemostasis
clotting - blood converted into solid gel (platelets, RBCs, plasma)
occurs around platelets, reinforces plug
vital hemostatic defense mechanism
anticoagulant drugs
warfarin
heparins
direct oral anticoagulants
hirudins
Virchow’s triad
- circulatory stasis
- hypercoagulable state
- epithelial cell injury
high risk for clots
= need for anticoagulation
example of circulatory stasis
atrial fibrillation
immobilization
deep vein thrombosis
example of hypercoagulable state
malignancy
deficiencies in anti-clotting factors
pregnancy
example of epithelial cell injury
trauma
fractures
surgery
heart valve replacement
coagulation
a proteolytic cascade involving serine proteases
complex of Va with negative phospholipids on aggregating platelets provides binding site for Xa + thrombin
binding requires Ca2+ + carboxyglutamic acid residues
warfarin
vitamin K reductase antagonist
enzyme needed to carboxylate factors II, VII, IX, X
problems with warfarin
rapid peak plasma concentration after ingestion but delayed pharmacological effect (requires depletion of clotting factors)
wide individual variation
teratogenic
need to monitor clotting time (INR)
many drug interactions
↑ bleeding risk - narrow TI
unwanted effects: bleeding, liver damage
heparins
first extracted from liver
IV or subq admin
neg charged sulfated glycosaminoglycands
rapid onset of action
used to bridge warfarin therapy
unwanted effects: bleeding, heparin-induced thrombocytopenia/thrombosis
mech of action:
bind ATIII via unique pentasaccharide sequence
induce conformational change in ATIII = ↑ affinity for active site of factors IIa, Xa
unfractionated + low molecular weight
direct oral anticoagulants
rivaroxaban
dabigatran etexilate (prodrug but metabolised rapidly in plasma)
hirudins
specific thrombin inhibitor
thrombolytic/fibrinolytic drugs
recombinant tPA
streptokinase
most common cancers
in males: prostate, colorectal
in females: breast, colorectal
cancer
group of 100+ diseases that develop across time
can develop in any of body’s tissues
both hereditary and environmental factors contribute to its development
develops due to loss of growth control in cells as a result of mutations in genes involved in cell cycle control
hereditary mutations
inherited/germ-line mutations
gene changes that come from a parent and exist in all cells of the body
5-10% of cancers
acquired mutations
sporadic/somatic mutations
environmental influences such as exposure to radiation or toxins, not passed on to offspring
multiple-hit hypothesis
Knudson hypothesis
normally, the body can compensate for one mutation → second mutation is the cause of effects
if hereditary: only one additional mutation is required
proto-oncogenes
genes that normally control how often cell divides and the degree to which it differentiates
oncogenes
mutated proto-oncogenes = cause normal cells to grow out of control and become cancer cells
permanently turned on or activated = continuous division
classes of oncogenes
growth factors
growth factor receptors
signal transducers
transcription factors / nuclear transducers
programmed cell death regulators
tumor suppressor genes
normal genes that slow down cell division, repair DNA mistakes, and tell cells when to die
~30: p53, BRCA1, BRCA2, APC, RB1
genes that control cell division (RB1)
genes that repair DNA (HNPCC)
cell “suicide” genes (p53)
cancer development
cell with genetic mutation → uncontrolled proliferation = hyperplasia → loss of function = dysplasia → dedifferentiation = in situ cancer → invasiveness = invasive cancer → metastasis
invasive cancer - other mutations
- production of metalloproteinases to break down extracellular matrix
- telomerase expression = ↑ cell division
- factors to cause growth of local blood vessels
tumor directed angiogenesis
triggered when solid tumors exceed 2 mm3 and become hypoxic
secrete factors to attract blood vessel growth
= transition from hyperplasia to neoplasia
fundamental issues of chemotherapy
- cancer is often far advanced by the time of detection
- they are your own cells
- cannot leave any cancer cells behind after treatment ends
- most cancer chemotherapy drugs target proliferating cells
- chemo drugs target rapidly dividing cells
- solid tumor heterogeneity
- development of drug resistance
- cancer is often far advanced by the time of detection
~30 cell doublings = cell mass with a diameter of 2 cm → within limits of diagnostics but might be unnoticed
another 10 doublings would be ~20 cm = lethal tumor mass
neoplasm is silent for first 3/4+ of its existence
- they are your own cells
there can be little reliance on the host immunological defense mechanisms in ridding the body of the cancer cells
anything that kills cancer cells is likely to also affect normal cells
- cannot leave any cancer cells behind after treatment ends
a given therapeutic dose of a cytotoxic drug destroys a constant fraction of the malignant cells
a dose that kills 99.99% of cells used to treat a tumor with 10^11 cells will still leave 10 million viable malignant cells
- most cancer chemotherapy drugs target proliferating cells
cells need to be actively proliferating for effective tx
most sensitive in S phase
- chemo drugs target rapidly dividing cells
any rapidly dividing cell in the body will be impacted by the agents
- bone marrow toxicity
- impaired wound healing
- hair loss
- GI epithelium damage
- depression of growth in children
- sterility
- teratogenicity
- solid tumor heterogeneity
3 layers: A = outside, C = inner mass
A - dividing cells, continuously in cell cycle
B - resting cells = G0
C - cells are no longer able to divide, contribute to tumor vol
- development of drug resistance
- ↓ drug uptake due to ↓ expression of transporter
- ↑ drug efflux due to upreg of efflux pumps
- change in drug metabolism (↓ activation of prodrug)
- ↑ DNA damage repair
- ↑ resistance to apoptosis
- change in drug target or target levels
cell cycle
G0: rest
G1: growth
S: synthesis, replication of DNA
G2: growth
M: division
primary drug resistance
present when the drug is first given
acquired drug resistance
result from either adaptation of the tumor cells or mutation
i. mutant is not affected by tx → continues to grow
ii. persister cells after tx have innate resistance → more sensitive to mutations after tx
alkylating agents
originated from mustard gas and nitrogen mustard
alkylation: transfer of an alkyl group from one molecule to another
form highly reactive, positively charged (electrophilic) intermediates
alkyl groups bind covalently to DNA
bifunctional = cross link DNA
*myelosuppression
nitrogen mustards, nitrosoureas, cisplatin
myelosuppression
↓ production of RBCs, WBCs, platelets
nitrogen mustards
cannot cross BBB
only targets cells in S phase
substitutions alter PK → different drug distribution
*myelosuppression, immunosuppression, hemorrhagic cystitis
mechlorethamine, chlorambucil, melphalan
cyclophosphamide
CMF or IMF
treatment of breast cancer after surgery
cyclophosphamide/ifosfamide, methotrexate, fluorouracil
nitrosoureas
require activation in the liver to reactive intermediates
lipid soluble = can penetrate CNS → brain tumors
*myelosuppression, leukomogenic, hepatotoxicity
carmustine, lomustine
alkyl sulfonate
forms G-G and G-A intra-strand crosslinks
selective effects on blood forming cells (myelosuppression)
used in high doses for bone marrow transplantation
busulfan
triazines
used for glioblastomas + melanomas
N-7 or O-6 positions of G
dacarbazine, temozolomide
ethylenimines
lymphoma + cancers of breast, ovary, bladder
used to treat malignant effusions
thiotepa
resistance to alkylating agents
↓ transport across cell membrane
↑ [thiol]i (↓ efficacy of alk. agents)
↑ enz detoxification of reactive intermediates
↑ DNA repair
MGMT
DNA repair enzyme
if MGMT promoter region is methylated, cells no longer produce MGMT = more responsive to alkylating agents
methylation of MGMT promoter in gliomas = predictor of responsiveness to triazines
platinum complexes
bifunctional
passive diffusion or copper transporter to enter cell
hydrolyzed due to ↓ [Cl-]i = trapped
reacts with DNA to form intrastrand cross links = stops replication
cisplatin
cell cycle non-specific
renal toxicity due to generation of ROS in kidney by metabolism
nausea + vomiting
resistance: ↓ uptake + retention, ↑ DNA repair, ↑ production of cellular thiols
PEB
cisplatin, etoposide, bleomycin
treatment of testicular cancer: >90% cures
antimetabolites
mimic natural metabolites
interfere with biosynthetic pathways
inhibit critical steps in nucleic acid synthesis
cell cycle specific = S phase
toxicity due to effects on proliferating cells: myelosuppression, GI toxicity, hair loss
why are antimetabolites less carcinogenic than alkylating agents
administration
continuous IV infusion = constant level → lower peak concentrations
folate cycle
formation of thymidine nucleotide
DHF (FH2) → THF (FH4) → DHF
= dUMP → dTMP → dTTP
interfere with cycle = alter ratio of nucleotides → affect DNA synthesis
inside cells, folate + MTX converted to polyglutamates
osteogenic sarcoma
HDMTX + leucovorin rescue
* oral + GI ulceration, myelosuppression, pulmonary infiltrates/fibrosis
selectivity of leucovorin rescue
tumor cells upregulate efflux pumps = remove leucovorin from cells
accumulates in normal cells = conversion of FH4
mechanisms of resistance to MTX
↓ uptake via folate transporters
↑ MTX efflux
altered target enzymes
↓ polyglutamation
↑ thymidine uptake (competes w effect of MTX)
pyrimidine analogues
antimetabolites that mimic structure of metabolic pyrimidines
interfere with enzymatic interaction
suicide substrate
compound that binds enzyme + triggers conformational change to intermediate state = permanent block of enzymatic activity
FdUMP → inhibits TS
specific thymidylate synthase inhibitors
Raltitrexed: transported into cells via folate transporters, fully active after polyglutamation
potent inhibitor of TS (100x higher than 5-FU)
cytadine analogues
pyrimidine nucleosides → modification of ribose
Cytarabine + Gemcitabine
prodrugs → requires phosphorylation to activate
incorporation into DNA = inhibit polymerization
resistance to araC
↓ uptake via nucleoside transporters
↑ activity of cytidine deaminase
↓ activity of dCK
change in activity of DNA polymerase = less affected
dFdC action
phosphorylated to dfdCDP → irreversible inhibition of ribonucleotide reducase
dFdCTP is incorporated into DNA → inhibits DNA polymerase
metabolism of thiopurines
6-MP enters cell through ENBT1
either inactivated or converted:
- inhibition of de novo purine synthesis (TPMT)
- incorporation into DNA → apoptosis
6-TG → incorporated into DNA = apoptosis
TPMT
thiopurine methyltransferase
pharmacogenomics = high individual variability → ↓ or absent enz activity (5%: normal dose is toxic)
↑ TGN metabolites = higher myelosuppression
screen prior to admin of 6-MP
DNA topoisomerases
unwind helix for DNA replication + RNA transcription
present at elevated levels in tumors
type I topoisomerase
change degree of supercoiling of DNA
ss breaks + religation
topI
type II topoisomerase
ds breaks
topIIa, topIIb
topoisomerase inhibitors
- inhibit religation step = locks enzyme in cleavage complex (↑ rate of cleavage)
- competitive inhibition of ATP binding site in type II - prevents ATP-hydrolysis to drive enz action
- inhibition of DNA topoisomerase binding
- inhibit ATP hydrolysis and DNA release at last step
FOLFIRI
5-FU, leucovorin, Irinotecan
tx of colon cancer
irinotecan (CPT-11) pharmacogenomics
SN-38 inactivated by UGT1A1
- 10% of caucasians have ↓ fxn variant = poor metabolism, toxicity
- ↑ expression = resistance
CPT-11 inactivated by CYP3A4
- ↑ expression = resistance
anthracyclins
inhibition of topII = DNA strand breakage → apoptosis
intercalative binding to DNA, partial unwinding
*free radical formation by generation of OH and O2- → cell membrane damage, large CV effects
cell cycle non specific
toxicity of anthracyclins
myelosuppression
GI irritation
cardiac toxicity
- delayed = related to cumulative lifetime dose
resistance to anthracyclins
- ↑ DNA repair
- ↑ efflux
- inactivation (type II metabolism)
- ↓ apoptosis (↓ apoptotic proteins + ↑ antiapoptotic proteins)
podophyllotoxin derivatives
semi-synthetic glycoside derivatives
non-intercalating inhibitor of topII
forms stabilized complex with topII-DNA
single + double strand breaks
late S/early G2
etoposide resistance
↑ efflux
↓ binding to topII
↑ glutathione conjugation
microtubules
play a role in cellular structural support (component of cytoskeleton)
important roles in formation + function of mitotic spindles, axonal transport of organelles
dynamic structure: add and remove subunits
antimicrotubule agents
interfere with formation and function of microtubules
stabilizers = blocks dissolution (-)
destabilizers = blocks assembly (+)
side effects: nausea + abdominal discomfort
vinca alkaloids
bind to tubulin at the end of microtubules and to tubulin dimers
destabilizers = dissolution of mitotic spindles (no cell division), inhibit organelle transport
cell cycle specific: G1/S phase
vinca alkaloid resistance
↑ efflux through ABC transporters
taxanes
stabilizers: bind to tubulin = enhance polymerization
= discrete bundles of stable microtubules, inhibit cell replication
cell cycle specific: G2/M phase
hormonal therapy
tx that adds, blocks, or removes hormones
tissues like breast, prostate, endometrial rely on hormones (androgens + estrogens) for proliferation
non cytotoxic drugs → slow down cancer growth, used in combination with other chemo
effects mediated through ER and PR
targeting ER action in breast cancer
i. aromatase inhibitors = block ligand
ii. antiestrogens, SERMs = block R activation
iii. small molecule inhibitors = block R interaction with DNA
iv. peptides + small molecules block coactivators
Tamoxifen + SSRIs
SSRIs used to treat hot flashes (side effect of tamoxifen)
anti-CYP2D6 activity = drug competition → ↓ tamoxifen efficacy
hormonal therapy for prostate cancer
DHT modulates prostate growth → binds to cytoplasmic androgen Rs → activation, transport to nucleus → binds HRE in gene promoters
80% is AR+ = androgen-sensitive
androgen withdrawal therapies
↓ androgen production
- bilateral orechidectomy
- medical castration
- GnRH antagonists
- androgen synthesis inhibitors
androgen R antagonism
GnRH antagonist
↓ activity of system
rapid castration (96h)
no flare
8.9% PSA failure
40% local injection reaction
monthly administration
GnRH agonist
↓ activity of system
slow castration (3-4 weeks)
flare → stim of system = worsens first
14.1% PSA failure
1% local injection reaction
administration every 3 months
molecularly targeted therapeutics
interfere with specific molecular target that plays role in tumor growth or progression
more selective than previous therapies = ↓ side effects
epidermal growth factor receptors
(receptor tyrosine kinases)
activation enhances proliferative capabilities of cancer cells:
- self sufficiency in growth signals
- insensitivity to anti-growth signals
- evasion from apoptosis
- limitless replication potential
- sustained angiogenesis
- tissue invasion and metastasis
inhibition of RTK
- block ligand binding to receptor
- block receptor dimerization
- induce receptor endocytosis and degradation via ubiquitination
- block tyrosine kinase activity
HER2 receptors
EGRF family of RTKs
amplification of gene = ↑ proliferative capacity
↑ HER2 = poor prognosis
target for anti-cancer therapeutics:
- MCAB against extracellular domain
- TK inhibitors of intracellular enz activity of R
problems with Ab approach to HER2 R
dose limiting systemic toxicities (some EGFR is necessary for normal fxn)
skin rashes + diarrhea
high molecular weight = slow + incomplete distribution
requires IV
elicits immune response
targeting one specific R = too specific
tyrosine kinase inhibitors
solution to over-specificity
block phosphorylation step
chronic myeloid leukemia
Philadelphia chromosome: chromosomal translocation = genetic recombination to combine BCR-ABL tyrosine kinase
activates mediators of cell cycle regulation
= growth factor is constitutively active → high level of proliferation
imatinib resistance
BCR-ABL overexpression
BCR-ABL kinase mutation (↓ binding affinity)
BCR-ABL independent mechanisms
TKI vs Abs
TKI
- orally admin
- low MW = rapid distribution
- broader spectrum of kinases (cross react)
- lack immune responses
- severe side effects
Abs
- IV admin
- specific
- downregulate Rs = dual activity
angiogenesis inhibitors
prevent metastasis
monoclonal Abs against vascular endothelial growth factor A and R = starves tumor cell of oxygen/nutrients
proteasomes
degradation of unneeded or damaged proteins
tag protein by linkage to ubiquitin
critical for cell cycle inhibition
action blocked by proteasome inhibitors
