DM2 Insulin Replacement therapy preparations

o Lispro /Aspart = Most soluble and most rapid

Glucose tox mechanisms o Soluble/regular = rapid absorb
o Covalent add of glucose to proteins o NPH = Int. absorb Mixed w/ protamine
o Increase gluc leads to accum of oxidants o Lente = slow Amorphous insulin zinc suspension.
o Osmotic effects o Ultralente = very slow insulin zinc suspension
Long term complications o Glargine = peakless ultra long acting
o CV = atherosclerosis/MI/Stroke precipitate at sub cut site.
o Retinopathy o Regimen
o Nephropathy Mixture of different prearations using both
o Neuropathy = deterioration of peripheral motor and rapid and slow.
sensory in long axons Insulin pump
Type 1 DM o Adverse Rxn
o Insulin dependent Hypoglycemia =
o Juvenile onset sweat/tremor/confusion/coma/death
o Def in insulin production due to destruction of B
cells T2Dm Treatments assuming pt still capable of making insulin.
o Tx is by insulin replacement If not, need to use T1DM replacement therapy
o Pt presents as starvation
o Protein/FA used for gluconeogenesis Metformin
o Ketone bodies are main energy source o Doesnt stim insulin release (no risk of
o Lead to Ketoacidosis hypoglycemia)
o Weight Loss
Type 2
o Actions = Reduce Gluconeogenesis from liver and
o Non insulin dependent
enhanced insulin action peripherals (insulin
o Can produce insulin early T2DM is insulin w/
resistance)
glucose
o MOA = Indirectly activate AMPK (enzyme that is
o Insulin resistance = reduced tissue sensitivity
activated during exercise)
pancreas insulin production to maintain
o SE = GI / Lactic acidosis
euglycemia.
o Can comb w/ sulfonylurea = synergy
Those who cant maintain normal gluc get
T2DM. Sulfonylurea = Glimperide/Glipizide/Glyburide
o B cells continue to decline resulting in insulin def. o Pt must be able to make insulin
o Obesity linked to insulin resistance o MOA = (-) ATP sensitive K+ channel on B cell
Fat makes Resistin that causes insulin depol insulin release (mimic glucose)
resistance. o Absorb in GI and protein bound
o SE = May cause hypoglycemia (long half
Morning Blood Glucose levels
life)/weight gain/loss of efficacy of drug w/ time
o Normal baseline fasting level is 90 mg/Dl.
and disease progression
o HbA1c = 4-6% is normal
Glitinides = Repaglinide/Nateglinide
Insulin
o Same MOA as sulfonylurea but rapid acting and
o Proinsulin is cleaved to make Peptide A linked via
short duration
disulfide to Peptide B. C peptide connects amino B
o No risk of hypoglycemia
w/ carboxy A terminal.
o Effects Thiazolidinediones (TZD/Glitazones) =
In Fat/muscle = GLUT4 Rosiglitazone/Pioglitazone
Fat metabolism o Only used when diet/exercise and metformin fail
o Potentiate insulin action on tissue (resist)
FA /TG synth in liver/fat
o MOA = Agon. Bind to peroxisomal proliferator
FA by lipolysis of fat TG
activated receptor (PPARy) in Fat tissue
protein synthesis
suppresses release of resistin from white adipose
o Mechanism
o SE = Weight gain/edema/CHF(both)/MI (rosi). No
Binds+TK2* cascade signaling.
MI/stroke w/ pioglitazone. Hepatoxicity (monthly
o Regulation
liver tests needed)
glucose B cell uptake glucose metab
o Not primary therapy but combo w/
ATP ATP (-) K+channel depol
metformin/sulfo/insulin.
Ca2+ open insulin exocytosis.
Incretins = GLP-1
Alpha 2 stim = (-) insulin release
o Insulin release also needs glucose levels so no risk
Beta 2 stim = (+) insulin release
of hypoglycemia
1st pass metab when insulin goes from
o 2 min half life
pancreas to liver
o Exanatide = GLP-1 homolog from Gila monster
Glucagon
Long half life and resisitant to DPP-4
o Reversal of diabetic coma to insulin overdose
protease that degrades GLP1
o Restore consciousness by raising blood glucose
o Liraglutide = GLP-1 from human w/ 1 AA change
Insulin Replacement Therapy More effective than exanatide
o Soluble/regular = Fast absorb into blood Weight loss (delay gastric emptying/blunt
o Insoluble = leach away from the subcutaneous appetite)
injection site slowly and provide baseline levels Depresses glucagon release
 In combo w/ sulfonyl risk of
hypoglycemia
o Sitagliptin = DPP-4 inhibitor
Increases half life of GLP
Oral instead of injection like exenatide
SE = acute pancreatitis/severe joint pain
Alpha-Glucosidase inhibitor = Acarbose/Miglitol
o intestinal glucose absorption
o SE = flatulence/diarrhea
o Used in combo
SGLT2 Inhibitors =
Dapagliflozin/Canagliflozin/Empaglifozin
o Inhibit renal glucose uptake by SGLT2
o Hypoglycemia not a risk b/c SGLT1 unimpaired
which is low capacity/high affinity
o SE = UT yeast infection /Diabetic ketoacidosis
Weight Loss Drugs
Bariatric surgery = most effective Tx
Orlistat
o Taken orally w/ meals. Only small amounts
absorbed
o MOA = (-) intestine Lipase that hydrolyze TG to
FA. TG remains undigested and elim in feces
o SE = Steatorrhea (aversion therapy)/malabsorption
of ADEK
Lorcaserin = 5-HT 2C Agonist
o MOA = acts via hypothalamic receptor POMC
(satiety hormone)
o SE = hallucinogenic
Phentermine/topiramate
o Stim/antiepileptic
o SE = paresthesia/cog diff
o Most stop after 1 year
o Sudden withdrawal = seizure
Bupropion/Naltrexone
o Atypical antidep/opioid antag
o Bupropion = Weak NE/DA reuptake inhibitor
o Naltrexone = opioid antag used for opioid/alc dep
o SE = Dont use in pregnant women or pts w/
seizure.
o It will HR and BP and should not be taken by pts
w/ uncontrolled hypertension
Liraglutide = injectable GLP-1
o Weight loss in obese pts and overweight w/
comorbities
o SE = Nausea/thyroid cancer/acute pancreatitis
Thyroid and Anti-Thyroid Drugs
Hormones
o T3 = triiodothyronine
o T4 = Thyroxine
Thyroid Hormone Action
o Increase metabolic rate
o Absence during devel. leads to Cretinism
Autoregulation
o Hypothal release TRH and Ant Pit relase TSH
Thyroid hormone receptor
o Nuclear receptor/transcription factor/steroid
receptor class
T3 vs T4
o Higher binding aff for T3
o Only T3 activates receptor
o Hormone regulates metabolism over long term, not
minute to minute
o Thyroid stored in thyroid as thyroglobulin
o T3 has shorter half life b/c binds not as tight to TBG
o T3/T4 bind tight to thyroxine binding globulin
(TBG). 99% is in bound form.
o Deiodinase enzymes in peripheral concert T4 to T3
and some T4 to reverse T3 (inactive)
o T4 can be considered as prohormone to T3
Hormone Synthesis
o Iodide form absorbed from blood by follicular cells.
(radioisotopes also absorbed bad if nuclear
explosion, Tx w/ sodium iodide)
o Iodine from diet
Lack hypothyroidism/goiter
Enlargement due to gland scavenging for
iodide
o Once absorbed iodide oxidized and attached to
tyrosine (on thyroglobulin) using Thyroperoxidase
o Thyroglobulin contains 100 tyrosine residues
which are used for T4 synthesis.
o Iodination 1) added to 3 position (MIT) and then
to 5 position (DIT)
Steps are target for Thioureylene drugs
o T4 is made by combining 2 DITs
o Iodine modified Thyroglobulin secreted out of
follicular cells into extracellular colloid
Thyroid hormone secretion
o T3/T4 moieties remain attached to thyroglobulin in
colloid
o Colloid take up by phagocytosis into a lysososme
where T3 and T4 are released into blood
o TSH stimulates iodide uptake/mods/release
o TSH contributes to devel of Goiter (seen in both
hypo and hyper)
Thyroid function tests
o Free thyroxine (FT4)
Total serum levels of T4 (TT4) measured
but hard b/c most bound to TBG
Free throxine index (FTI) gives a derived
number using indirect assess of FT4 from
fractional bound state of TBG
o TSH levels
By ELISA/RIA
Small changes in FT4 are amplified into
large changes in TSH
Best measure of thyroid function
o Anti-Thyroid antibodies
 Hypo/hyperthyroid can come from
autoimmune disease
Serum tested for reactivity w/ diff thyroid
antigens
thyro=peroxidase/thyroglobulin/TSH
receptor
Hypothyroidism
o Cretinism = when hypo present from borth
Dwarfism/mental retardation
T4 replacement at birth can fix this
o Hashimotos Thyroiditis
Most common cause
Idiopath auto immune impairment to the
thyroid T4/T3 synth/release
o Def of iodine goiter
o Destruction of thyroid, due to
Surgery
Radioactive iodine therapy
Long term progression of Graves
o Therapy
Supp w/ Sodium Iodide if dietary def
Otherwise, Tx w/ Thyroxine replacement
o Thyroid hormone replacement
Absorbed orally in Gi
Levothyroxine = Synthetic T4
Liothyronine sodium = Synthetic T3
T4 is cheaper and will become T3 in vivo
T3 is more potent and used for
Hypothyroidic coma
Once daily T4 pill
SE = over treatment results in
hyperthyroidal symptoms.
Elderly Afib
Post menopause Osteoporosis
Hyperthyroidism Graves Disease
o Thyrotoxicosis
o Thyroid storm = sudden acute symptoms.
Sometimes w/ severe Tachy/Afib or failure
o Due to auto-immune disorder
Antibodies to TSH receptor mimic TSH
and constantly stimulate production of
thyroid hormone also a cause of goiter
o Treatment
Anti-thyroid drugs Block synthesis
Ablation of gland w/ radioactive 131I
Surgical resection of thyroid
All 3 have potential in making pt
hypothyroid state
o SE
Propylthiouracil hepatic failure
Therefore, Methimazole is preferred 1st
line
o Partial Surgical Removal
Results in hypothyroidism and must take
thyroxine replacement therapy for life
o Partial destruction w/ radioactive iodine
Preferred and most common Tx for Graves
Pt ingests Sodium Iodide
Pt should not be taking antithyroid drugs
Varying levels of hypothyroid results and
will have to take T4 replacement therapy
Dont take if Preg, and young men and
women who have concerns over infertility
and cancer
o High doses of Iodide
(-) of thyroid hormone release
Hyper symptoms decerase in 2 days and
thyroid vasc and size decreased in 2 weeks
Comb w/ Thionamides to (-) thyroid
hormone synthesis that may occur w/
iodide
Effect only temporary, not useful for long
term
Use for thyroid storm
Use Pre-op to reduce size before removing
thyroid
o Propranolol (or other beta blockers)
Gives only symptomatic relief of tachy,
arrhythmias, tremors
Useful during the lag period in
thioureylene therapy
Control thyroid storm
o Thyroid Storm Tx
Beta blocker
High conc of Iodide
Propylthiouracil

Antithyroid Drugs

Thioureylenes = Methimazole/Propylthiouracil
o (-) tyrosyl iodination acting as substrate for
iodination by thyroid peroxidase
o Methimazole = most common, long half life pill
o Propylthiouracil
also (-) peripheral deiodination of T4 to T3
Tx acute thyroid storm
Main use long term stabilization
o Synthesis of hormone stops w/ in 12 hours but
symptoms take up to 4 months to stop
Slow turn over of pre-existing hormones
Large thyroid stores
Once stores are depleted, dose should be
decreased otherwise will result in
hypothyroid
Gonadal Given to pts w/ E2 def b/c of ovarian
Estrogens dysgenesis, dwarfism,
hypopituitarism/castration.
Chemical Structure/Function Begun at puberty age of 11ish
o Most potent naturally occurring estrogen is 17B- Post menopausal HRT
Estradiol o After menses stopped, there is a E2 for years
o Natural Estrogens are 18C w/ phenolic A ring/OH at o Indication for therapy = hot flashes, sweating, high
C3, and B-hydroxy or ketone at C17 risk of osteoporosis
o Phenol A ring needed for selective high affinity o risk of osteoporosis is most in smokers who are
binding to receptor thin, white, inactive, w/ a low Ca2+ intake and
o If given orally, its metab in liver and ineffective family Hx of osteoporosis
o Ethinyl estradiol are protected against liver metab o E2 admin in a cycle (3 weeks on, 1 week off) using
and can be given orally smallest dose
o Nonsteroidal = Diethylstilbestrol Given w/ progesterone
Synthesis o Prophylaxis of E2 in postmenopausal osteoporosis
o Androstenedione or T become estrogen using Best if Tx strated before bone loss occurs
Aromatase, a p450 dependent monooxygenease But not usually need b/c
CYP. Only 35% develop osteopor
This makes the A ring Exercise and Ca2+ diet also good
o Granulosa cells = main source of Estradiol (E2) in SE of E2
premenopausal women In women w/ oophorectomy/hysterectomy,
o In men and post menopausal its Fat this Tx is fine b/c no risk of endometrial
o During pregnancy its placenta cancer
MOA Adverse effects of E2
o Regulate transcription of genes o Post menopausal bleeding
o Enters cell by passive diff and binds nuclear Use smallest dose in cyclic fashion
estrogen receptor So if bleeding happens it will be during
o Once receptor is bound, it binds specific DNA withdrawal
sequences o Nausea/breast tender/hyperpigmentation/migraine,
Physiologic Effects cholestasia, hypertension
o At pubery GnRH released in pulsatile + o In post menopausal, risk of endometrial cancer
FSH/LH release w/ progestational agent, risk
o After 2 years, enough estrogen for endometrial o Endometrial cancer in pre-menopausal risk when
changes given estrogen + progestin
o estrogen can exert neg feedback on hypothalamus o Breast cancer w/ oral contraceptive
to GnRH release and thus FSH from pit. Contraindication
Effect on Pit LH is biphasic midcycle o Pts w/ estrogen dependent neoplasm like uterine
surge in LH ovulation cancer/breast cancer
o When ovaries are removed or are non-fxnal o unDx genital bleeding/liver disease/Hx of
Menstrual bleeding induced by admin and thromboembolism
subsequent stop of E2. o First Trimester Pregnancy
Can be induced by a single large dose or Drugs
by small doses for weeks o Natural
Dosage w/ in a defined range can result in Estradiol
menstrual flow even in absence of E2 Esradiol salts
withdrawal = Threshold dose Conjugated estrogens
When E2 is given w/o interruption and a o Synthetic
brief admin of progesterone Diethylstilbestrol
menstruation Ethinyl Estradiol
o Metabolic actions Alternative therapy
Cause salt and water retention edema. o Soy food
Water retention seen in latter half of cycle
Can LDL and HDL but also coag Progestins
factors that cause BP and sodium/water
retention Structure/Function
E2 thus causes an risk of CV disease o Needs ketone on A ring
Bioavailability o Substituents on C17 affect bio activity
o Absorbed via skin, mucous, GI tract Synthesis
o Oral limited b/c of liver metab o LH +Progesterone made in corpus luteum during
Therapeutic use 2nd half of cycle just before ovulation
o Oral Contraception o If ovum fertilized implantation trophoblast
o Postmenopausal Hormone Replacement Therapy makes hCG sustaining corpus luteum
(HRT) o 2nd/3rd month of preg, placenta makes estrogen and
o Primary hypogonadism progesterone
Physio Actions
 o Prog release during cycle secretory endometrium Anti-estrogens
Abrupt decline in Prog means onset of
menses These include agents that
o Porg needed to maintain Preg, suppress menses and o Comp antag of E2 receptor
uterine contractility o (-) of E2 synth (eg, aromatase inhib)
o During preg, Prog + E2 prolif of mammary acini. o Agents that cause oppostive physio effects
o Prog secretion causes 1 degree C at midcycle (progestins and androgens)
before ovulation Comp antag of E2 receptor
MOA o Tamoxifen
o Nuclear receptor o Clomiphen
Absorption o Activated by hydroxyl at C4 of A ring
o Absorb in GI but metab by liver so not good orally Trans = antiestrogen
o Ethinyl moiety at C17 prevents degredation Cis = estrogen agonist
Therapeutic use o Effects
o Oral Contraception Ovary enlargement
o HRT see above Disrupts Neg feedback gonadotropin
o Endometriosis release gametogenesis steroidgen
To regress ectopic endometrial growth Clomphen Tx infertility
o Metastatic endometrial carcinoma Tamoxifen Tx E2 dep breast cancer
Palliative measure in recurring carcinoma risk of endometrial/uterine
Drugs cancer b/c its also a partial agonist
o Medroxyprogesterone Other antiestrogens
o Norethindrone o Leuprolide
o Norgestrel w/ cont use GnRH receptors
o Ethynodiol desensitized gonadotropin and steroid
release
Oral Contraceptives also used as anti-androgen
Aromatase inhibitor
Types o Anastrozole/Letrozole/Exemestane
o Combination = E2 + prog o Steroidal agent = Exemestane = suicide inhibitor of
o Biphasic and triphasic = E2 + Prog, where Prog aromatase
varies during cycle o Nonsteroidal = Letrozole/Anastrozole = interact
o Subcutaneous Progestin implant = Norgesterol reversibly w/ heme groups of CYPs (aromatase)
Long lasting o In post menopausal E2 conc is very high in the
o Single entity breast carcinoma b/c there are lots of aromatase in
Progetin alone = minipill those tumors.
Diethylstilbestrol = morning after pill Does not risk of endometrial/uterine
Nausea/vomit cancer
Norgestrel/ethinyl estradiol o In pre menopausal Letrozole used successfully
Norgestrel alone for induction of ovulation in an infertile woman
Single 600 mg mifepristone o Males have E2 levels like post penopausal women
MOA o Male breast cancer expresses E2/Prog receptor
o Inhbiti ovulation Tx w/ tamoxifen
o Suppress FSH and LH
o E2 (-) FSH release Antiprogestins
o Prog (-) E2 induced LH
Mifepristone
Adverse
o Der of Norethindrone
o CV
o Comp antag acts at Prog and glucocorticoid receptor
Thrombophlebitis/thromboembolism
o Action
Plateletl aggregation
Admin @ follic phase (-) ovulation by
Cerebral/coronary thrombosis
blocking Prog receptor at Pit/hypothal
Mild hypertension
mortality/morbidity Mid cycle surge of gonadotropins
o Cancer is suppressed and follicular
Vag/uterine/breast carcinoma development delayed
Hepatoma Admin at luteal phase block Prog action
Endometrial/cervical cancer in on uterus Prostaglandin release from
premenopausal on E2 only contraceptive endometrium and subsequent bleeding
Gluccocorticoid antag can be used to Tx
risk if comb w/ prog
Cushings
These induce metab of oral contracptives = effect
o Therapeutic use
o Rifampin/penicillin/tetracycline
Abortifacient in early preg when comb w/
o Anti HIV
Prostaglandin
o Entiepileptic
Single 600 mg dose use as post sex
o St. john wort
contraceptive
 Use on progesterone sensitive tumors Adverse effects
Lipopristone used o Virilizing effects
In women masculinization
Androgens Acne, hair, voice, menses irregular
Long Tx can cause male pattern baldness,
T main hormone for men muscle, hypertrophy of clit
T made in ovary and adrenal cortex in women In children epiphyseal closure
T a prohormone for 2 classes Azoospermia due to inhiiton of
o 5a-reduced androgens = DHT gonadotropin secretion and conversion of
o Estrogens androgens to estrogens
Structure/function o Feminizing effect
o Oral ineffective b/c of liver metab Gynecomastia in men
o Esterification of 17B-hydroxy group = polarity = Aromatization to E2
solubility in parenteral admin Toxicity
o Alkylation of 17a inhibits hepatic metab and then o Edema w/ sodium retention
given orally o Jaundice
Synthesis Cholestatic hepatitis
o Conc of T high in males during o Long term Tx hepatic adenocarcinoma
Embryogenesisneonatal Drugs
Puberty o Testosterone
o LH/FSH regulate testicle growth/spermatogenesis o Testosterone salts
and steroidogenesis o Oxandrolone
o T can suppress LH and FSH release via feedback o Methyltestosterone
inhib of GnRH o Fluoxymesterone
DHT (aromatase) Estradiol used for o Danazol
neg feedback
Physio effects Anti-Androgens
o Anobolic effects
In hypogonadal/castrated men, admin of To manage hyperplasia and carcinoma of prostate
androgens urinary excretion of Tx virilization of females, precocious puberty
N/K/Na/Cl Leuprolide = GnRH analog/agonist
Nitrogen retention is seen to be used for o Cont Tx = LH and T secretion b/c desensitize
male muscle pattern GnRH receptors
o Anabolic and androgenic effects result from diff o Initially cause surge of T use finasteride so you
responses to the same hormone in diff tissues cut down the effect of T or use androgen receptor
o All anabolic steroids are androgenic antag
MOA o 1 week later, GnRH get desensitized stop making
o Androgen receptor gene regulation T
Therapeutic uses 2 other types
o Hypogonadism o Comp antags for androgen receptor
If testicle failure is complete, therapy w/ o Synthesis inhibitors
long acting T esters admin IM Finasteride
If begun at puberty, normal development o Inhibits 5a-reductase needed to make DHT
Will not respond to androgen therapy Cyproterone acetate
unless growth hormone also included o Comp antag of DHT for androgen receptor
o Catabolic state o Tx hirsutism
Improve nitrogen balance post Flutamide/Bicalutamide
surgery/injury o Non steroidal anti androgens
o Athletic performance o Comp antags
Promote muscle growth immature boys o Flutamide Tx of prostate cancer w/ leuprolide
and women of all ages o Bicalutamide = less hepatoxic than flutamide
But not really in mature men Abiraterone acetate
You would need massive doses to o Converted to abiraterone inhibits T synth by
have effect in mature men inhbiting CYP17A1 (17 alpha hydroxylase)
But androgen receptor in mature o Tx castration resistant prostate cancer
men are functionally saturated Spironolactone
o Stim of erythropoiesis o Comp antag
Effect on erythropoietin o Tx female hirsutism
Tx refractory anemia
Used in bone marrow fail, myelofib and
renal fail
o Carcinoma of breast
Palliatve Tx of breast cancer in
premenopausal women
Acting as an enti-estrogen
GnRH and GnRH antagonist

MOA
o GnRH analog (Leuprolide or Nafarelin) desensitize
GnRH receptors and cause the reduction of
estrogens
o GnRH antag (Cetrorelix) directly reduce estrogen
formation by blocking GnRH receptors
Endometriosis
o Caused by excess estrogen created each month
o Leuprolide (GnRH analog) use w/ low dose
hormone replacement therapy to diminish bone loss
o Nafarelin (GnRH) Nasal preparation
o Cetrorelix acetate (GnRH Antag)
Uterine fibroids
o May present w/ endometriosis
o Have estrogen receptors
o Leuprolide Used to decrease size before removal
by surgery
o Nafarelin same
o Cetrorelix acetate (GnRH Antag)

Oxytocin

During 2nd half of preg uterine muscle show an in

Oxytocin receptors.
Oxytocin stimulate uterine contraction
Used for labor induction
Acts via G protein/PIP/Ca2+ to contact uterine smooth
muscle
Stimulates release of prostaglandins and leukotrienes that
help uterine contraction
Clinical uses
o Pre-mature labor is helped by hydration to lower
plasma conc of oxytocin
o Oxytocin Antag Atosiban suppress preterm labor
5FU mechanisms and Uses Capecitabine
o Pre-pro drug of 5FU
5FU = 5 Flourouracil o Use in refractory breast cancer
Severe mucositis o tox when compared to 5FU w/ leucovorin
5FU MOA interferes w/ o Substitute for 5FU in patients receiving radiation
o Thymidine Synthesis via thymidylate synthase o Not affected by liver metab
o RNA function via incorporation into RNA Tegafur
o DNA synthesis via incorporation in to DNA TAS 114 inhibits DPD and dUTPase
5FU -> FUR (w/ ribose) -> into RNA S-1 mechanism
5FU FUdR (w/ deoxyribose) FdUMP interferes w/ o Mix of 3 drugs
DNA synthesis Tegafur (5FU prodrug)
Action of leucovorin Competitive DPD inhibitor
o Acts as a activated folic acid Inhibitor of 5FU phosphorylation in FU
o Gets a methyl from folate potassium oxonate
o dUMP dTMP (thymidine) using TS 5 FU resistance
o TS is inhib by 5FU o Thymidylate synthase
o FdUMP and leucovorin form a ternary complex w/ High levels may overcome the block from
TS, blocking the conversion of dUMP to thymidine FU
Orally = low bio peak b/c 50% cleared by liver o DPD
o Toxic to gut diarrhea High levels may degrade 5FU
5FU toxicity o Thymidine phosphorylase
o Hand foot syndrome High levels may degrade 5FdUMP
Palmar-plantar erythrodysesthesia o Patients w/ low levels of all 3 enzymes
Due to 5FU IV continuous (DPD/TS/TP) responded to 5FU therapy
5FU drug interactions High TS + Irinotecan still responded even
o Leucovorin = efficacy and toxicity though TS was high
o Uridine = toxicity Conclusion
o Thymidine o 5FU and tox are dose and schedule dependent
tox if given after o Many other compounds can interact w/ 5FU to alter
tox if given before or w/ 5 FU efficacy and to
o High level of folate in diet would tox o Pro drugs of 5FU may offer advantage of 5FU
Mechanism of Resistance o Using genetic tests may predict tox and efficacy
o Deletion of enzymes involed in activation o Understanding the PK of 5FU is of great importance
o Increased catabolism
o Def o folate cofactor
o Decrease incorporation into DNA/RNA Pharmacology of Anti-Tumor Agents
Metabolism
o Dihydropyrimidine Dehydrogenase (DPD) break Fine print
down 5FU o As population ages, cancer becomes more common
Highest in liver o Most prevalent tumors are often the most difficult to
Presence in intestine interferes w/ treat
absorption of oral 5FU o New drugs are appearing but optimal efficacy needs
Genetic def 5FU toxic screening
o DPD deficiency Cancer treatment
Heterozygote and homozygote experience o Prevention
severe tox o Early DX
Exon 14 mutation o Therapy
Use exhalation of 13C-CO2 after ingestion Surgery/radiation/drugs
of 13C-Uracil to test pt for DPD def Pharm
If you see no 13C-CO2 pt is o Drugs used at max tolerated dose to maximize
DPD def tumor eradication
o Toxicity to Flouropyrimidines (5FU) Tumors recur locally even after microscopically complete
Dose might just be too high resection
Uridine Triacetate = antidote for overexposure Effective Drug target DNA synthesis
o Uridine competes w/ 5FU for RNA incorporation o Toxicity to rapidly dividing cells like GI, bone
Uridine acetate is an oral uridine pro drug marrow
thats 8x more active than uridine o Sdf
Ethynyluracil Slow growing tumor
o Inhibits DPD activity o Anti DNA therapy limited use here
o Converts 5FU to orally active form Fast growing tumors embryonic/lymphoma/leukemia
o Prolongs 5FU half life through inhibition of o Less than 30 day doubling = drug responseiveness
catabolism Slow tumors lung/breast/colon
o DPD gets irreversibly inactivated by ethynyluracil o More than 80 day
o Pretreatement w/ Ethynl causes a renal clearance o Unresponsive to DNA therapy
of 5FU + Ethynyluracil compared to 5FU alone Angiogenesis is needed for cont growth of tumor
 Major classes o Treat slow dividing cells unresponsive to
o Antimetabolites = inhibit DNA synth (DNA antimetabolites
analogs/fast growing tumors) o Cross links DNA malignant cells cannot repair
o Alkylating agents (impair DNA function/Slow the DNA
growing tumors too) o Agents are analogs of Nitrogen mustard (HN2)
o Antibiotics (often DNA binders) Melphalan
o Hormone antags Cyclophosphamide (CTX)
o Enzyme Antags/Monoclonal Ab Chlorambucil
Antimetabolites All but HN2 itself, are powders
o MTX o Cyclophosphamide
DNA synth needs U T using a 1C Broad no cycle specificity
transfer Eradicate marrow before transplant
Transfer inhibited by MTX Req activation by liver
Cells die Bladder toxicity MESNA protects the
MTX inhibits Dihydrofolic reductase that bladder
is used to make DHFA THFA (where o MESNA
THFA is used to convert dUMP to dTMP) Detoxifies cytotoxic products of CTX in
Rate of transport into leukemic cells is bladder
important o Temolozolomide
Give Flourouracil (FdUMP) before giving Brain tumor/X BBB
MTX, otherwise there wont be TS for the Base pair mismatch gets mistaken for
fDUMP to act on thymidine
Long term low dose FU is correct dose o Cis-platinum
o Cytosine Arabinoside (Ara-C) DNA cross linker
S phase specific Warps DNA
Needs to be phosphorylated overcome o Resistance
by high dose of Ara-C Decreased entry into cell/increase loss
Effective against some leukemias from cell
Unexpected CNS tox related to Drug inactivated in cell
glycoprotein metab Enhanced DNA repair after alkylation
o Gemcitabine o Summary
Broader spectrum Preferential attack on DNA guanines
Small lung cancer Cross link impairs strand separation
Pancreatic cancer Impairs DNA/RNA synth.
Radiation sensitizer Response by lack of repair enzymes
Targets G0/G1 cells accumulation of S
phase Actinomycin D
Inhibits ribonucleotide reductase o Intercalates into 2 base pairs
o Nucleosides purines/pyrimidines o Warps structure
Anti metabolites o Cannot replicate
AraC Bleomycin
FU o No marrow tox
6-MP o Drug conc in lung/skin pulm fibrosis and skin
Must be phosphorylated to be effective lesions
Toxicities involve inhibition of DNA Daunorubicin/Doxorubicin = Anthracyclines
synthesis in rapidly dividing cells o Free radical warps DNA
o 6 mercaptopurine o Tox to bone marrow and heart muscle
Phosphorylation leads to antimetabolite Vinca Alkyloids
Impairs purine synth and DNA synth o Vincristine
Tx leukemia, lymphoma o Vinblastine
Allopurinol inhibits 6-MP metabolism and o Tx leukemia and solid tumors
promotes 6-MP tox o Binds to microtubule dimers and inhibits formation
o Allopurinol so mitotic arrest
Inhibits uric acid formation Taxol
Useful when urate builds up in o Ovarian
chemotherapy o Binds tubulin, precents cell division and prolif
Inhibits 6-MP metabolism so should not be Topoisomerase inhibitors
used w/ it o Camptothecin = Topo 1 inhib
o Antimetabolites are analogs of something else o Etoposide = Topo 2 inhib
5FU = Uracil For solid tumors
Arabinoside = cytosine Major tox in GI/marrow but not heart
6MP = adenine Multi Drug resistance = MDR
MTX = folic acid o Transport system that pumps drugs out of cells and
Alkylating Agents protective to normal cells
o Missing in malignant cells
 o When malignant get MDR resistant to anti tumor
agents
Inhibition of MDR
o drug response in tumor cells w/ MD
o But MDR is also protecting many normal host cells
from tox so not useful
Antitumor antibiotics
o Some are DNA binders but do not form covalent
bonds w/ DNA
o Others affect chromatin fxn topoisomerase and
microtubule inhibitors
o Active w/o metab
o MDR is a common mode of resistance
New targets
o Slow growing solid tumors
o Promote immunoligc response
o Tumor specific kinase nd growth factor
o Angiogenesis inhibitors
Tyrosine Kinase Inhibitors
o Gleevac (CML)
o Iressa (non SS lung)
o Tykerb (breast ca)
Monoclonals
o Erbitux targets EGRF needed to maintain growth
o Avastin targets VEGF needed for angiogenesis
o Herceptin targets Her2/neu
Why Drug combinations
o Dif modes of host tox
o Kill dividing and non dividing tumor cells
o Effective for cells resisitant to a single drug
o Delay development of resistance
o Potentiate effects
Combinations
o MTX tox to leukemia and marrow
o VCR toxic to leukemia and PNS
o Pred toxic to leukemia
o 6 MP toic to leukemia and immune
Impediments to success
o Slow tumor cell doubling time
o Enhanced repair of induced damage
o High levels of drug inactivating enzymes
o Enhanced outward drug transport
o Loss of inward drug transport
Modes of drug tox
o S phase drugs GI and marrow (rapid dividing
cells)
o Dose related
High AraC = CNS
Low dose 5FU = hand/foot
o Unexpected
Anthracyclines/vincas
o Sites of conc
Bleomycin skin/lung
CTX Liver
Cis-platin Kidney
Targeting the Pathway o Pertuzumab blocks dimerization
Breast Cancer
o Monoclonal Abs usualy used in combo w/ other drugs o T-DM1
o Oral TK inhibs usually monotherapy Tox is usually rash o Antibody drug conjugate
and diarrhea o Uses trastuzumab as a delivery vehicle
o VEGF antibodies o DM1 Antimicrotubule
o Large molecules o T-DM1 selectively delivers DM1 to HER2
o Extracellular domain positive tumor cells
o Bind to ligands/receptors o Breast cancer
o Given IV o CTLA-4 pathway
o Bevacizumab o Checkpoint inhibitors
Colon Cancer o Found on surface of helper T cells
Lung Cancer o CTLA4 sends an inhibitory signal to T cells and
Kidney cancer CD28 sends a simulatory signal
Glioblastoma o CTLA4 inhib = Ipilimumab
Tox For Melanoma
Hypertension Toxicity = Any immune mediated side
Thromboembolic effect
Bleeding/wound healing o PD-1/PD-L1 activation
o VEGF TKI o Acts as down regulator by preveting activation of T
o Small molecule cells
o Intracell o Promotes apoptosis in antigen specific T cells
o Impede downstream o Anti PD1
o Given orally Nivolumab
o Insert into ATP binding pockets or can impede TK Melanoma
access to molecular caperone system leading to Tox GI/Fatigue/Hepatic enzyme
degredation problem
o Sunitinib
Inhibit downstream signals
Kidney Cancer
Tox
Rash/Diarrhea
Fatigue
o EGFR Activation
o Activation via cross talk w/ other receptors
(dimerization)
o EGFR monoclonal Ab
o Cetuximab
Blocks ligand induced phosphorylation of
EGFR
Induces apoptosis and ADCC1
Pt needs to express KRAS wild type
metastatic colorectal cancer
Mutation in KRAs causes colon cancer
Wild Type KRAS EGFR causes colon
cancer and can be attacked by Cetuximab
Tox = Rash
Skin rash shows drug is working
on tumor cells
o EGFR TKI
o Erlotinib blocks downstream events in lung cancer
mutation
Seen in female, Asian, non smoker
Tox Rash but not that bad
Rash shows drug is working
o Her-2 Pathway
o Receptors activated by ligand induced dimerization
(homo/hetero) activate TK
o Trastuzmab Monoclonal AB blocks receptor
Early stage breast cancer
Tox = cardiotoxicty
o Lapatinib TKI inhibits downstream events
Breast Cancer and can get into brain
Diarhea
Hand foot syndrome
Pediatric Pharmacology Infants have higher body fat relative to
adults
o Absorption Infants have higher body fat and total body
o Cutaneous Absorption water which means that Vd of both fat
Increased in infancy, due to soluble and water soluble meds is higher
Cutaneous layers compared to adults
Level of hydration o Clearance
Cutaneous perfusion of epidermis o Gray baby syndrome w/ chloramphenicol
Higher proportion of body surface o Metabolism
area to mass Fetal life, CYPs are half of adult amount
Even more in premature neonates Post natal time, they reach adult amount by
o Intramuscular Absorption 1 year
Not preferred in pediatrics Hepatic metab of most drugs is less in
Drug needs enough Lipophilicity to be neonates/infants
absorbed through tissues into capillaries But metabolism can be higher than
Must also retain enough water solubility to Carbamezpeine is clearance is higher in
prevent precipitation children as reflected by higher dose and a
shorter interval b/w doses
Linking phosphate to phenytoin
Sulfate conjugation is efficient in infants
increases its water solubility and
Biotransformation of durgs such as
can be absorbed IM
morphine, nsaids, apap, bilirubin proceed
Enough blood flow and muscle activity
via glucouronidation. Hepatic capacity for
Inactive critically ill pt has
glucouron is poorly developed early on in
reduced absorp compared to
fetal and neonatal life
healthy active pt
o Elimination
o GI absorption
o Decreased drug elim in newborn
Gastric pH is higher in neonates
o GFR equals adult at 2 years
Reaches pH of 3 by 4 months
o Specialty
Acid labile will be readily absorbed
o Tetracyclines
Weak acids need larger doses
Dont use under 8 years teeth
GI surface area is greater
discoloration
GI integrity is intact in a full term, in a pre-
o FQ
mature it offers a less absorptive barrier
Tendon problems and poor cartilage
Not homogenous
development
Absorption is slower in neonates than older
o Ceftriaxone
children
Displace bilirubin from albumin in
Anticonvulsants given rectally
premature infants and neonates w/
BZ have a lipophil and pKA that
hyperbilirubinemia and results in
is good for absorption rectally
kernicterus
o Intravenous Absorption
o PD
No differences Seen
o
o Pediatric Preparations
o Ingestion of a suspension with its larger surface area
to volume ratio results in a faster transport and
shorter lag to peak serum conc compared to pill
o Distribution
o Volume of Distribution (Vd) = most important PK
parameter that affects distribution
Refelects apparent space in body
o For any given drug, the apparent Vd will differ from
pt to pt based on protein binding, body com that has
significant age related diff, mostly due to alterations
in total body water
o Total body water
Greater in neonates/infants than adults
Extracellular compartment larger also
To achieve comparable conc of drugs that
distribute in total body water, higher doses
of per Kg body weight must be given to
infants/children than adults
o Protein Binding
Albumin and alpha1-acid glycoprotein
Neonates/infants have decreased protein
binding
o Fat distribution